Peptidomimetic macrocycles

Description

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Apr. 24, 2016, is named 35224-766.301_SL.txt and is 1,202,889 bytes in size.

BACKGROUND OF THE INVENTION

The human transcription factor protein p53 induces cell cycle arrest and apoptosis in response to DNA damage and cellular stress, and thereby plays a critical role in protecting cells from malignant transformation. The E3 ubiquitin ligase MDM2 (also known as HDM2) negatively regulates p53 function through a direct binding interaction that neutralizes the p53 transactivation activity, leads to export from the nucleus of p53 protein, and targets p53 for degradation via the ubiquitylation-proteasomal pathway. Loss of p53 activity, either by deletion, mutation, or MDM2 overexpression, is the most common defect in human cancers. Tumors that express wild type p53 are vulnerable to pharmacologic agents that stabilize or increase the concentration of active p53. In this context, inhibition of the activities of MDM2 has emerged as a validated approach to restore p53 activity and resensitize cancer cells to apoptosis in vitro and in vivo. MDMX (MDM4) has more recently been identified as a similar negative regulator of p53, and studies have revealed significant structural homology between the p53 binding interfaces of MDM2 and MDMX. The p53-MDM2 and p53-MDMX protein-protein interactions are mediated by the same 15-residue alpha-helical transactivation domain of p53, which inserts into hydrophobic clefts on the surface of MDM2 and MDMX. Three residues within this domain of p53 (F19, W23, and L26) are essential for binding to MDM2 and MDMX.

There remains a considerable need for compounds capable of binding to and modulating the activity of p53, MDM2 and/or MDMX. Provided herein are p53-based peptidomimetic macrocycles that modulate an activity of p53. Also provided herein are p53-based peptidomimetic macrocycles that inhibit the interactions between p53, MDM2 and/or MDMX proteins. Further, provided herein are p53-based peptidomimetic macrocycles that can be used for treating diseases including but not limited to cancer and other hyperproliferative diseases.

SUMMARY OF THE INVENTION

Described herein are stably cross-linked peptides related to a portion of human p53 (“p53 peptidomimetic macrocycles”). These cross-linked peptides contain at least two modified amino acids that together form an intramolecular cross-link that can help to stabilize the alpha-helical secondary structure of a portion of p53 that is thought to be important for binding of p53 to MDM2 and for binding of p53 to MDMX. Accordingly, a cross-linked polypeptide described herein can have improved biological activity relative to a corresponding polypeptide that is not cross-linked. The p53 peptidomimetic macrocycles are thought to interfere with binding of p53 to MDM2 and/or of p53 to MDMX, thereby liberating functional p53 and inhibiting its destruction. The p53 peptidomimetic macrocycles described herein can be used therapeutically, for example to treat cancers and other disorders characterized by an undesirably low level or a low activity of p53, and/or to treat cancers and other disorders characterized by an undesirably high level of activity of MDM2 or MDMX. The p53 peptidomimetic macrocycles can also be useful for treatment of any disorder associated with disrupted regulation of the p53 transcriptional pathway, leading to conditions of excess cell survival and proliferation such as cancer and autoimmunity, in addition to conditions of inappropriate cell cycle arrest and apoptosis such as neurodegeneration and immunedeficiencies. In some embodiments, the p53 peptidomimetic macrocycles bind to MDM2 (e.g., GenBank® Accession No.: 228952; GI:228952) and/or MDMX (also referred to as MDM4; GenBank® AccessionNo.: 88702791; GI:88702791).

In one aspect, provided herein is a peptidomimetic macrocycle comprising an amino acid sequence which is at least about 60%, 80%, 90%, or 95% identical to an amino acid sequence chosen from the group consisting of the amino acid sequences in Table 1, Table 1a, Table 1b, or Table 1c. Alternatively, an amino acid sequence of said peptidomimetic macrocycle is chosen from the group consisting of the amino acid sequences in Table 4. In some embodiments, the peptidomimetic macrocycle is not a peptide as shown in Table 2a or 2b. In other cases, the peptidomimetic macrocycle does not comprise a structure as shown in Table 2a or 2b. In some embodiments, the peptidomimetic macrocycle has an amino acid sequence chosen from Table 1. In some embodiments, the peptidomimetic macrocycle has an amino acid sequence chosen from Table 1a. In some embodiments, the peptidomimetic macrocycle has an amino acid sequence chosen from Table 1b. In some embodiments, the peptidomimetic macrocycle has an amino acid sequence chosen from Table 1c.

Alternatively, an amino acid sequence of said peptidomimetic macrocycle is chosen as above, and further wherein the macrocycle does not include a thioether or a triazole. In some embodiments, the peptidomimetic macrocycle comprises a helix, such as an α-helix. In other embodiments, the peptidomimetic macrocycle comprises an α,α-disubstituted amino acid. A peptidomimetic macrocycle can comprise a crosslinker linking the α-positions of at least two amino acids. At least one of said two amino acids can be an α,α-disubstituted amino acid.

In some embodiments, provided are peptidomimetic macrocycle of the formula:

embedded image

wherein:

each A, C, D, and E is independently an amino acid;

B is an amino acid,

embedded image

[—NH-L₃-CO—], [—NH-L₃-SO₂—], or [—NH-L₃-];

R₁and R₂are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R₁and R₂forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids;

R₃is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R₅;

each L or L′ is independently a macrocycle-forming linker of the formula -L₁-L₂-;

L₁and L₂and L₃are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R₄—K—R₄—]_n, each being optionally substituted with R₅;

each R₄is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each K is O, S, SO, SO₂, CO, CO₂, or CONR₃;

each R₅is independently halogen, alkyl, —OR₆, —N(R₆)₂, —SR₆, —SOR₆, —SO₂R₆, —CO₂R₆, a fluorescent moiety, a radioisotope or a therapeutic agent;

each R₆is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;

R₇is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R₅, or part of a cyclic structure with a D residue;

R₈is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R₅, or part of a cyclic structure with an E residue;

v and w are independently integers from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10;

u is an integer from 1-10, for example 1-5, 1-3 or 1-2;

x, y and z are independently integers from 0-10, for example the sum of x+y+z is 2, 3, or 6; and

n is an integer from 1-5.

In some embodiments, w>2 and each of the first two amino acid represented by E comprises an uncharged side chain or a negatively charged side chain.

some embodiments, the first C-terminal amino acid and/or the second C-terminal amino acid represented by E comprise a hydrophobic side chain. For example, the first C-terminal amino acid and/or the second C-terminal amino acid represented by E comprises a hydrophobic side chain, for example a large hydrophobic side chain.

In some embodiments, w is between 3 and 1000. For example, the third amino acid represented by E comprises a large hydrophobic side chain.

In other embodiments, the peptidomimetic macrocycle as claimed excludes the sequence of:

(SEQ ID NO: 1)

Ac-RTQATF$r8NQWAibANle$TNAibTR-NH₂,

(SEQ ID NO: 2)

Ac-RTQATF$r8NQWAibANle$TNAibTR-NH₂,

(SEQ ID NO: 3)

Ac-$r8SQQTFS$LWRLLAibQN-NH₂,

(SEQ ID NO: 4)

Ac-QSQ$r8TFSNLW$LLAibQN-NH₂,

(SEQ ID NO: 5)

Ac-QS$r5QTFStNLW$LLAibQN-NH₂,

or

(SEQ ID NO: 6)

Ac-QSQQ$r8FSNLWR$LAibQN-NH₂.

In other embodiments, the peptidomimetic macrocycle as claimed excludes the sequence of: Ac-Q$r8QQTFSN$WRLLAibQN-NH2 (SEQ ID NO: 7).

Peptidomimetic macrocycles are also provided of the formula:

embedded image

wherein:

- each of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀is individually an amino acid, wherein at least three of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀are the same amino acid as the amino acid at the corresponding position of the sequence Phe₃-X₄-His₅-Tyr₆-Trp₇-Ala₈-Gln₉-Leu₁₀-X₁₁-Ser₁₂(SEQ ID NO: 8), where each X is an amino acid;

each D and E is independently an amino acid;

each L or L′ is independently a macrocycle-forming linker of the formula -L₁-L₂-;

L₁and L₂are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R₄—K—R₄—]_n, each being optionally substituted with R₅;

R₃is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R₅;

each R₄is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each K is O, S, SO, SO₂, CO, CO₂, or CONR₃;

each R₅is independently halogen, alkyl, —OR₆, —N(R₆)₂, —SR₆, —SOR₆, —SO₂R₆, —CO₂R₆, a fluorescent moiety, a radioisotope or a therapeutic agent;

each R₆is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;

v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10;

w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and

n is an integer from 1-5.

In some embodiments, a peptidomimetic macrocycle has the Formula:

embedded image

wherein:

each of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀is individually an amino acid, wherein at least three of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀are the same amino acid as the amino acid at the corresponding position of the sequence Phe₃-X₄-Glu₅-Tyr₆-Trp₇-Ala₈-Gln₉-Leu₁₀/Cba₁₀-X₁₁-Ala₁₂(SEQ ID NO: 9), where each X is an amino acid;

each D is independently an amino acid;

each E is independently an amino acid, for example an amino acid selected from Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine);

each L or L′ is independently a macrocycle-forming linker of the formula -L₁-L₂-;

R₃is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R₅;

each R₄is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each K is O, S, SO, SO₂, CO, CO₂, or CONR₃;

each R₅is independently halogen, alkyl, —OR₆, —N(R₆)₂, —SR₆, —SOR₆, —SO₂R₆, —CO₂R₆, a fluorescent moiety, a radioisotope or a therapeutic agent;

each R₆is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;

v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10;

w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and

n is an integer from 1-5.

In some embodiments, a peptidonimetic macrocycle has the Formula:

embedded image

wherein:

each of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀is individually an amino acid, wherein at least two of Xaa₃, Xaa₅, Xaa₆, Xaa₈, Xaa₉, and Xaa₁₀are the same amino acid as the amino acid at the corresponding position of the sequence Phe₃-X₄-Glu₅-Tyr₆-Trp₇-Ala₅-Gln₉-Leu₁₀/Cba₁₀-X₁₁-Ala₁₂(SEQ ID NO: 9), where each X is an amino acid;

each D and E is independently an amino acid;

each L or L′ is independently a macrocycle-forming linker of the formula -L₁-L₂-, wherein L comprises at least one double bond in the E configuration;

R₃is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R₅;

each R₄is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each K is O, S, SO, SO₂, CO, CO₂, or CONR₃;

each R₅is independently halogen, alkyl, —OR₆, —N(R₆)₂, —SR₆, —SOR₆, —SO₂R₆, —CO₂R₆, a fluorescent moiety, a radioisotope or a therapeutic agent;

each R₆is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;

v is an integer from 1-1000;

w is an integer from 3-1000;

n is an integer from 1-5; and

Xaa₇is Boc-protected tryptophan.

In some embodiments of any of the Formulas described herein, [D]_vis -Leu₁-Thr₂. In other embodiments of the Formulas described herein, each E other than the third amino acid represented by E is an amino acid selected from Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine).

In some embodiments, w is an integer from 3-10, for example 3-6, 3-8, 6-8, or 6-10. In some embodiments, w is 3. In other embodiments, w is 6. In some embodiments, v is an integer from 1-10, for example 2-5. In some embodiments, v is 2.

In some embodiments, peptides disclosed herein bind a binding site defined at least in part by the MDMX amino acid side chains of L17, V46, M50, Y96 (forming the rim of the pocket) and L99. Without being bound by theory, binding to such a binding site improves one or more properties such as binding affinity, induction of apoptosis, in vitro or in vivo anti-tumor efficacy, or reduced ratio of binding affinities to MDMX versus MDM2.

In some embodiments, the peptidomimetic macrocycle has improved binding affinity to MDM2 or MDMX relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In other instances, the peptidomimetic macrocycle has a reduced ratio of binding affinities to MDMX versus MDM2 relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In still other instances, the peptidomimetic macrocycle has improved in vitro anti-tumor efficacy against p53 positive tumor cell lines relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In some embodiments, the peptidomimetic macrocycle shows improved in vitro induction of apoptosis in p53 positive tumor cell lines relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In other instances, the peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle has an improved in vitro anti-tumor efficacy ratio for p53 positive versus p53 negative or mutant tumor cell lines relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In some instances the improved efficacy ratio in vitro, is 1-29, ≥30-49, or ≥50. In still other instances, the peptidomimetic macrocycle has improved in vivo anti-tumor efficacy against p53 positive tumors relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In some instances the improved efficacy ratio in vivo is −29, ≥30-49, or ≥50. In yet other instances, the peptidomimetic macrocycle has improved in vivo induction of apoptosis in p53 positive tumors relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In some embodiments, the peptidomimetic macrocycle has improved cell permeability relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In other cases, the peptidomimetic macrocycle has improved solubility relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2.

In some embodiments, Xaa₅is Glu or an amino acid analog thereof. In some embodiments, Xaa₅is Glu or an amino acid analog thereof and wherein the peptidomimetic macrocycle has an improved property, such as improved binding affinity, improved solubility, improved cellular efficacy, improved cell permeability, improved in vivo or in vitro anti-tumor efficacy, or improved induction of apoptosis relative to a corresponding peptidomimetic macrocycle where Xaa₅is Ala.

In some embodiments, the peptidomimetic macrocycle has improved binding affinity to MDM2 or MDMX relative to a corresponding peptidomimetic macrocycle where Xaa₅is Ala. In other embodiments, the peptidomimetic macrocycle has a reduced ratio of binding affinities to MDMX vs MDM2 relative to a corresponding peptidomimetic macrocycle where Xaa₅is Ala. In some embodiments, the peptidomimetic macrocycle has improved solubility relative to a corresponding peptidomimetic macrocycle where Xaa₅is Ala, or the peptidomimetic macrocycle has improved cellular efficacy relative to a corresponding peptidomimetic macrocycle where Xaa₅is Ala.

In some embodiments, Xaa₅is Glu or an amino acid analog thereof and wherein the peptidomimetic macrocycle has improved biological activity, such as improved binding affinity, improved solubility, improved cellular efficacy, improved helicity, improved cell permeability, improved in vivo or in vitro anti-tumor efficacy, or improved induction of apoptosis relative to a corresponding peptidomimetic macrocycle where Xaa₅is Ala.

In some embodiments, the peptidomimetic macrocycle has an activity against a p53+/+ cell line which is at least 2-fold, 3-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, or 100-fold greater than its binding affinity against a p53−/− cell line. In some embodiments, the peptidomimetic macrocycle has an activity against a p53+/+ cell line which is between 1 and 29-fold, between 30 and 49-fold, or ≥50-fold greater than its binding affinity against a p53−/− cell line. Activity can be measured, for example, as an IC50 value. For example, the p53+/+ cell line is SJSA-1, RKO, HCT-116, or MCF-7 and the p53−/− cell line is RKO-E6 or SW-480. In some embodiments, the peptide has an IC50 against the p53+/+ cell line of less than 1 μM.

In some embodiments, Xaa₅is Glu or an amino acid analog thereof and the peptidomimetic macrocycle has an activity against a p53+/+ cell line which is at least 10-fold greater than its binding affinity against a p53−/− cell line.

Additionally, a method is provided of treating cancer in a subject comprising administering to the subject a peptidomimetic macrocycle. In some embodiments, the cancer is head and neck cancer, melanoma, lung cancer, breast cancer, or glioma.

Also provided is a method of modulating the activity of p53 or MDM2 or MDMX in a subject comprising administering to the subject a peptidomimetic macrocycle, or a method of antagonizing the interaction between p53 and MDM2 and/or MDMX proteins in a subject comprising administering to the subject such a peptidomimetic macrocycle.

Provided herein is a method of preparing a composition comprising a peptidomimetic macrocycle of

Formula (I):

embedded image

comprising an amino acid sequence which is about 60% to about 100% identical to an amino acid sequence selected from the group consisting of the amino acid sequences in Table 1, Table 1a, Table 1b, or Table 1c, the method comprising treating a compound of Formula (II)

embedded image

with a catalyst to result in the compound of Formula I

wherein in the compound(s) of Formulae (I) and (II)

each A, C, D, and E is independently an amino acid;

each B is independently an amino acid,

embedded image

[—NH-L₃-CO—], [—NH-L₃-SO₂—], or [—NH-L₃-];

each R₁and R₂are independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halogen; or at least one of R₁and R₂forms a macrocycle-forming linker L′ connected to the alpha position of one of the D or E amino acids;

each R₃is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R₅;

each L′ is independently a macrocycle-forming linker of the formula -L₁-L₂-;

each L₁, L₂and L₃are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R₄—K—R₄—]_n, each being optionally substituted with R₅;

each R₄and R_4′ is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each K is independently O, S, SO, SO₂, CO, CO₂, or CONR₃;

each R₅is independently halogen, alkyl, —OR₆, —N(R₆)₂, —SR₆, —SOR₆, —SO₂R₆, —CO₂R₆, a fluorescent moiety, a radioisotope or a therapeutic agent;

each R₆is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;

each R₇is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R₅, or part of a cyclic structure with a D residue;

each R₈is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R₅, or part of a cyclic structure with an E residue;

each v and w are independently integers from 1-1000;

u is an integer from 1-10;

each x, y and z are independently integers from 0-10;

each n is independently an integer from 1-5;

each o is independently an integer from 1 to 15;

each p is independently an integer from 1 to 15;

“(E)” indicates a trans double bond; and

one or more of the amino acids A, C and/or B when B is an amino acid, present in the compounds of Formulae (I) and (II), has a side chain bearing a protecting group.

In some embodiments, the protecting group is a nitrogen atom protecting group.

In some embodiments, the protecting group is a Boc group.

In some embodiments, the side chain of the amino acid bearing the protecting group comprises a protected indole.

In some embodiments, the amino acid bearing the protecting group on its side chain is tryptophan (W) that is protected by the protecting group on its indole nitrogen. For example, the protecting group is a Boc group.

In some embodiments, after the step of contacting the compound of Formula II with catalyst the compound of Formula (I) is obtained in equal or higher amounts than a corresponding compound which is a Z isomer. For example, after the step of contacting the compound of Formula II with catalyst the compound of Formula (I) is obtained in a 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold higher amount than the corresponding compound which is a Z isomer.

In some embodiments, the catalyst is a ruthenium catalyst.

In some embodiments, the method further comprises the step of treating the compounds of Formula (I) with a reducing agent or an oxidizing agent.

In some embodiments, the compound of Formula (II) is attached to a solid support. In other embodiments, the compound of Formula (II) is not attached to a solid support.

In some embodiments, the method further comprises removing the protecting group(s) from the compounds of Formula (I).

In some embodiments, the ring closing metathesis is conducted at a temperature ranging from about 20° C. to about 80° C.

In some embodiments, the peptidomimetic macrocycle of Formula (I) has the Formula:

embedded image

wherein:

each of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀is individually an amino acid, wherein at least two of Xaa₃, Xaa₅, Xaa₆, Xaa₈, Xaa₉, and Xaa₁₀are the same amino acid as the amino acid at the corresponding position of the sequence Phe₃-X₄-His₅-Tyr₆-Trp₇-Ala₈-Gln₉-Leu₁₀-X₁₁-Ser₁₂(SEQ ID NO: 8), where each X is an amino acid;

each D and E is independently an amino acid;

each L or L′ is independently a macrocycle-forming linker of the formula -L₁-L₂-, wherein L comprises at least one double bond in the E configuration;

R₃is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R₅;

each R₄is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each K is O, S, SO, SO₂, CO, CO₂, or CONR₃;

each R₅is independently halogen, alkyl, —OR₆, —N(R₆)₂, —SR₆, —SOR₆, —SO₂R₆, —CO₂R₆, a fluorescent moiety, a radioisotope or a therapeutic agent;

each R₆is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;

v is an integer from 1-1000;

w is an integer from 3-1000;

n is an integer from 1-5; and

Xaa₇is Boc-protected tryptophan.

In some embodiments, the peptidomimetic macrocycle of Formula (I) comprises an α-helix.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

FIG. 1 shows a structure of peptidomimetic macrocycle 46 (Table 2b), a p53 peptidomimetic macrocycle, complexed with MDMX (Primary SwissProt accession number Q7ZUW7; Entry MDM4_DANRE).

FIG. 2 shows overlaid structures of p53 peptidomimetic macrocycles 142 (Table 2b) and SP43 bound to MDMX (Primary SwissProt accession number Q7ZUW7; Entry MDM4_DANRE).

FIG. 3 shows the effect of SP154, a peptidomimetic macrocycle, on tumor growth in a mouse MCF-7 xenograft model.

FIG. 4 shows the effect of SP249, a peptidomimetic macrocycle, on tumor growth in a mouse MCF-7 xenograft model.

FIG. 5 shows the effect of SP315, a peptidomimetic macrocycle, on tumor growth in a mouse MCF-7 xenograft model.

FIG. 6 shows the effect of SP252, a point mutation of SP154, on tumor growth in a mouse MCF-7 xenograft model.

FIG. 7 shows a plot of solubility for peptidomimetic macrocycles with varying C-terminal extensions.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “macrocycle” refers to a molecule having a chemical structure including a ring or cycle formed by at least 9 covalently bonded atoms.

As used herein, the term “peptidomimetic macrocycle” or “crosslinked polypeptide” refers to a compound comprising a plurality of amino acid residues joined by a plurality of peptide bonds and at least one macrocycle-forming linker which forms a macrocycle between a first naturally-occurring or non-naturally-occurring amino acid residue (or analog) and a second naturally-occurring or non-naturally-occurring amino acid residue (or analog) within the same molecule. Peptidomimetic macrocycle include embodiments where the macrocycle-forming linker connects the a carbon of the first amino acid residue (or analog) to the α carbon of the second amino acid residue (or analog). The peptidomimetic macrocycles optionally include one or more non-peptide bonds between one or more amino acid residues and/or amino acid analog residues, and optionally include one or more non-naturally-occurring amino acid residues or amino acid analog residues in addition to any which form the macrocycle. A “corresponding uncrosslinked polypeptide” when referred to in the context of a peptidomimetic macrocycle is understood to relate to a polypeptide of the same length as the macrocycle and comprising the equivalent natural amino acids of the wild-type sequence corresponding to the macrocycle.

As used herein, the term “stability” refers to the maintenance of a defined secondary structure in solution by a peptidomimetic macrocycle as measured by circular dichroism, NMR or another biophysical measure, or resistance to proteolytic degradation in vitro or in vivo. Non-limiting examples of secondary structures contemplated herein are α-helices, 3₁₀helices, β-turns, and β-pleated sheets.

As used herein, the term “helical stability” refers to the maintenance of α helical structure by a peptidomimetic macrocycle as measured by circular dichroism or NMR. For example, in some embodiments, a peptidomimetic macrocycle exhibits at least a 1.25, 1.5, 1.75 or 2-fold increase in α-helicity as determined by circular dichroism compared to a corresponding uncrosslinked macrocycle.

The term “amino acid” refers to a molecule containing both an amino group and a carboxyl group. Suitable amino acids include, without limitation, both the D- and L-isomers of the naturally-occurring amino acids, as well as non-naturally occurring amino acids prepared by organic synthesis or other metabolic routes. The term amino acid, as used herein, includes, without limitation, α-amino acids, natural amino acids, non-natural amino acids, and amino acid analogs.

The term “α-amino acid” refers to a molecule containing both an amino group and a carboxyl group bound to a carbon which is designated the α-carbon.

The term “β-amino acid” refers to a molecule containing both an amino group and a carboxyl group in a β configuration.

The term “naturally occurring amino acid” refers to any one of the twenty amino acids commonly found in peptides synthesized in nature, and known by the one letter abbreviations A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y and V.

The following table shows a summary of the properties of natural amino acids:

3-
1-

Side-chain

Letter
Letter
Side-chain
charge
Hydropathy

Amino Acid
Code
Code
Polarity
(pH 7.4)
Index

Alanine
Ala
A
nonpolar
neutral
1.8

Arginine
Arg
R
polar
positive
−4.5

Asparagine
Asn
N
polar
neutral
−3.5

Aspartic acid
Asp
D
polar
negative
−3.5

Cysteine
Cys
C
polar
neutral
2.5

Glutamic acid
Glu
E
polar
negative
−3.5

Glutamine
Gln
Q
polar
neutral
−3.5

Glycine
Gly
G
nonpolar
neutral
−0.4

Histidine
His
H
polar
positive (10%)
−3.2

neutral (90%)

Isoleucine
Ile
I
nonpolar
neutral
4.5

Leucine
Leu
L
nonpolar
neutral
3.8

Lysine
Lys
K
polar
positive
−3.9

Methionine
Met
M
nonpolar
neutral
1.9

Phenylalanine
Phe
F
nonpolar
neutral
2.8

Proline
Pro
P
nonpolar
neutral
−1.6

Serine
Ser
S
polar
neutral
−0.8

Threonine
Thr
T
polar
neutral
−0.7

Tryptophan
Trp
W
nonpolar
neutral
−0.9

Tyrosine
Tyr
Y
polar
neutral
−1.3

Valine
Val
V
nonpolar
neutral
4.2

“Hydrophobic amino acids” include small hydrophobic amino acids and large hydrophobic amino acids. “Small hydrophobic amino acid” are glycine, alanine, proline, and analogs thereof. “Large hydrophobic amino acids” are valine, leucine, isoleucine, phenylalanine, methionine, tryptophan, and analogs thereof. “Polar amino acids” are serine, threonine, asparagine, glutamine, cysteine, tyrosine, and analogs thereof. “Charged amino acids” are lysine, arginine, histidine, aspartate, glutamate, and analogs thereof.

The term “amino acid analog” refers to a molecule which is structurally similar to an amino acid and which can be substituted for an amino acid in the formation of a peptidomimetic macrocycle. Amino acid analogs include, without limitation, β-amino acids and amino acids where the amino or carboxy group is substituted by a similarly reactive group (e.g., substitution of the primary amine with a secondary or tertiary amine, or substitution of the carboxy group with an ester).

The term “non-natural amino acid” refers to an amino acid which is not one of the the twenty amino acids commonly found in peptides synthesized in nature, and known by the one letter abbreviations A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y and V. Non-natural amino acids or amino acid analogs include, without limitation, structures according to the following:

embedded image

Amino acid analogs include β-amino acid analogs. Examples of β-amino acid analogs include, but are not limited to, the following: cyclic β-amino acid analogs; β-alanine; (R)-β-phenylalanine; (R)-1,2,3,4-tetrahydro-isoquinoline-3-acetic acid; (R)-3-amino-4-(1-naphthyl)-butyric acid; (R)-3-amino-4-(2,4-dichlorophenyl)butyric acid; (R)-3-amino-4-(2-chlorophenyl)-butyric acid; (R)-3-amino-4-(2-cyanophenyl)-butyric acid; (R)-3-amino-4-(2-fluorophenyl)-butyric acid; (R)-3-amino-4-(2-furyl)-butyric acid; (R)-3-amino-4-(2-methylphenyl)-butyric acid; (R)-3-amino-4-(2-naphthyl)-butyric acid; (R)-3-amino-4-(2-thienyl)-butyric acid; (R)-3-amino-4-(2-trifluoromethylphenyl)-butyric acid; (R)-3-amino-4-(3,4-dichlorophenyl)butyric acid; (R)-3-amino-4-(3,4-difluorophenyl)butyric acid; (R)-3-amino-4-(3-benzothienyl)-butyric acid; (R)-3-amino-4-(3-chlorophenyl)-butyric acid; (R)-3-amino-4-(3-cyanophenyl)-butyric acid; (R)-3-amino-4-(3-fluorophenyl)-butyric acid; (R)-3-amino-4-(3-methylphenyl)-butyric acid; (R)-3-amino-4-(3-pyridyl)-butyric acid; (R)-3-amino-4-(3-thienyl)-butyric acid; (R)-3-amino-4-(3-trifluoromethylphenyl)-butyric acid; (R)-3-amino-4-(4-bromophenyl)-butyric acid; (R)-3-amino-4-(4-chlorophenyl)-butyric acid; (R)-3-amino-4-(4-cyanophenyl)-butyric acid; (R)-3-amino-4-(4-fluorophenyl)-butyric acid; (R)-3-amino-4-(4-iodophenyl)-butyric acid; (R)-3-amino-4-(4-methylphenyl)-butyric acid; (R)-3-amino-4-(4-nitrophenyl)-butyric acid; (R)-3-amino-4-(4-pyridyl)-butyric acid; (R)-3-amino-4-(4-trifluoromethylphenyl)-butyric acid; (R)-3-amino-4-pentafluoro-phenylbutyric acid; (R)-3-amino-5-hexenoic acid; (R)-3-amino-5-hexynoic acid; (R)-3-amino-5-phenylpentanoic acid; (R)-3-amino-6-phenyl-5-hexenoic acid; (S)-1,2,3,4-tetrahydro-isoquinoline-3-acetic acid; (S)-3-amino-4-(1-naphthyl)-butyric acid; (S)-3-amino-4-(2,4-dichlorophenyl)butyric acid; (S)-3-amino-4-(2-chlorophenyl)-butyric acid; (S)-3-amino-4-(2-cyanophenyl)-butyric acid; (S)-3-amino-4-(2-fluorophenyl)-butyric acid; (S)-3-amino-4-(2-furyl)-butyric acid; (S)-3-amino-4-(2-methylphenyl)-butyric acid; (S)-3-amino-4-(2-naphthyl)-butyric acid; (S)-3-amino-4-(2-thienyl)-butyric acid; (S)-3-amino-4-(2-trifluoromethylphenyl-butyric acid;

(S)-3-amino-4-(3,4-dichlorophenyl)butyric acid; (S)-3-amino-4-(3,4-difluorophenyl)butyric acid; (S)-3-amino-4-(3-benzothienyl)-butyric acid; (S)-3-amino-4-(3-chlorophenyl)-butyric acid; (S)-3-amino-4-(3-cyanophenyl)-butyric acid; (S)-3-amino-4-(3-fluorophenyl)-butyric acid; (S)-3-amino-4-(3-methylphenyl)-butyric acid; (S)-3-amino-4-(3-pyridyl)-butyric acid; (S)-3-amino-4-(3-thienyl)-butyric acid; (S)-3-amino-4-(3-trifluoromethylphenyl)-butyric acid; (S)-3-amino-4-(4-bromophenyl)-butyric acid; (S)-3-amino-4-(4-chlorophenyl)-butyric acid; (S)-3-amino-4-(4-cyanophenyl)-butyric acid; (S)-3-amino-4-(4-fluorophenyl)-butyric acid; (S)-3-amino-4-(4-iodophenyl)-butyric acid; (S)-3-amino-4-(4-methylphenyl)-butyric acid; (S)-3-amino-4-(4-nitrophenyl)-butyric acid; (S)-3-amino-4-(4-pyridyl)-butyric acid; (S)-3-amino-4-(4-trifluoromethylphenyl)-butyric acid; (S)-3-amino-4-pentafluoro-phenylbutyric acid; (S)-3-amino-5-hexenoic acid; (S)-3-amino-5-hexynoic acid; (S)-3-amino-5-phenylpentanoic acid; (S)-3-amino-6-phenyl-5-hexenoic acid; 1,2,5,6-tetrahydropyridine-3-carboxylic acid; 1,2,5,6-tetrahydropyridine-4-carboxylic acid; 3-amino-3-(2-chlorophenyl)-propionic acid; 3-amino-3-(2-thienyl)-propionic acid; 3-amino-3-(3-bromophenyl)-propionic acid; 3-amino-3-(4-chlorophenyl)-propionic acid; 3-amino-3-(4-methoxyphenyl)-propionic acid; 3-amino-4,4,4-trifluoro-butyric acid; 3-aminoadipic acid; D-β-phenylalanine; β-leucine; L-β-homoalanine; L-β-homoaspartic acid γ- benzyl ester; L-β-homoglutamic acid δ-benzyl ester; L-β-homoisoleucine; L-β-homoleucine; L-β-homomethionine; L-β-homophenylalanine; L-β-homoproline; L-β-homotryptophan; L-β-homovaline; L-Nω-benzyloxycarbonyl-β-homolysine; Nω-L-β-homoarginine; O-benzyl-L-β-homohydroxyproline; O-benzyl-L-β-homoserine; O-benzyl-L-β-homothreonine; O-benzyl-L-β-homotyrosine; γ-trityl-L-β-homoasparagine; (R)-β-phenylalanine; L-β-homoaspartic acid γ-t-butyl ester; L-β-homoglutamic acid δ-t-butyl ester; L-Nω-β-homolysine; Nδ-trityl-L-β-homoglutamine; Nω-2,2,4,6,7-pentamethyl-dihydrobenzofuran-5-sulfonyl-L-β-homoarginine; O-t-butyl-L-β-homohydroxy-proline; O-t-butyl-L-β-homoserine; O-t-butyl-L-β-homothreonine; O-t-butyl-L-β-homotyrosine; 2-aminocyclopentane carboxylic acid; and 2-aminocyclohexane carboxylic acid.

Amino acid analogs include analogs of alanine, valine, glycine or leucine. Examples of amino acid analogs of alanine, valine, glycine, and leucine include, but are not limited to, the following: α-methoxyglycine; α-allyl-L-alanine; α-aminoisobutyric acid; α-methyl-leucine; β-(1-naphthyl)-D-alanine; β-(1-naphthyl)-L-alanine; β-(2-naphthyl)-D-alanine; β-(2-naphthyl)-L-alanine; β-(2-pyridyl)-D-alanine; β-(2-pyridyl)-L-alanine; β-(2-thienyl)-D-alanine; β-(2-thienyl)-L-alanine; β-(3-benzothienyl)-D-alanine; β-(3-benzothienyl)-L-alanine; β-(3-pyridyl)-D-alanine; β-(3-pyridyl)-L-alanine; β-(4-pyridyl)-D-alanine; β-(4-pyridyl)-L-alanine; β-chloro-L-alanine; β-cyano-L-alanin; β-cyclohexyl-D-alanine; β-cyclohexyl-L-alanine; β-cyclopenten-1-yl-alanine; β-cyclopentyl-alanine; β-cyclopropyl-L-Ala-OH.dicyclohexylammonium salt; β-t-butyl-D-alanine; β-t-butyl-L-alanine; γ-aminobutyric acid; L-α,β-diaminopropionic acid; 2,4-dinitro-phenylglycine; 2,5-dihydro-D-phenylglycine; 2-amino-4,4,4-trifluorobutyric acid; 2-fluoro-phenylglycine; 3-amino-4,4,4-trifluoro-butyric acid; 3-fluoro-valine; 4,4,4-trifluoro-valine; 4,5-dehydro-L-leu-OH.dicyclohexylammonium salt; 4-fluoro-D-phenylglycine; 4-fluoro-L-phenylglycine; 4-hydroxy-D-phenylglycine; 5,5,5-trifluoro-leucine; 6-aminohexanoic acid; cyclopentyl-D-Gly-OH.dicyclohexylammonium salt; cyclopentyl-Gly-OH.dicyclohexylammonium salt; D-α,β-diaminopropionic acid; D-α-aminobutyric acid; D-α-t-butylglycine; D-(2-thienyl)glycine; D-(3-thienyl)glycine; D-2-aminocaproic acid; D-2-indanylglycine; D-allylglycine.dicyclohexylammonium salt; D-cyclohexylglycine; D-norvaline; D-phenylglycine; β-aminobutyric acid; β-aminoisobutyric acid; (2-bromophenyl)glycine; (2-methoxyphenyl)glycine; (2-methylphenyl)glycine; (2-thiazoyl)glycine; (2-thienyl)glycine; 2-amino-3-(dimethylamino)-propionic acid; L-α,β-diaminopropionic acid; L-α-aminobutyric acid; L-α-t-butylglycine; L-(3-thienyl)glycine; L-2-amino-3-(dimethylamino)-propionic acid; L-2-aminocaproic acid dicyclohexyl-ammonium salt; L-2-indanylglycine; L-allylglycine.dicyclohexyl ammonium salt; L-cyclohexylglycine; L-phenylglycine; L-propargylglycine; L-norvaline; N-α-aminomethyl-L-alanine; D-α,γ-diaminobutyric acid; L-α,γ-diaminobutyric acid; β-cyclopropyl-L-alanine; (N-β-(2,4-dinitrophenyl))-L-α,β-diaminopropionic acid; (N-β-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl)-D-α,β-diaminopropionic acid; (N-β-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl)-L-α,β-diaminopropionic acid; (N-β-4-methyltrityl)-L-α,β-diaminopropionic acid; (N-β-allyloxycarbonyl)-L-α,β-diaminopropionic acid; (N-γ-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl)-D-α,γ-diaminobutyric acid; (N-γ-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl)-L-α,γ-diaminobutyric acid; (N-γ-4-methyltrityl)-D-α,γ-diaminobutyric acid; (N-γ-4-methyltrityl)-L-α,γ-diaminobutyric acid; (N-γ-allyloxycarbonyl)-L-α,γ-diaminobutyric acid; D-α,γ-diaminobutyric acid; 4,5-dehydro-L-leucine; cyclopentyl-D-Gly-OH; cyclopentyl-Gly-OH; D-allylglycine; D-homocyclohexylalanine; L-1-pyrenylalanine; L-2-aminocaproic acid; L-allylglycine; L-homocyclohexylalanine; and N-(2-hydroxy-4-methoxy-Bzl)-Gly-OH.

Amino acid analogs include analogs of arginine or lysine. Examples of amino acid analogs of arginine and lysine include, but are not limited to, the following: citrulline; L-2-amino-3-guanidinopropionic acid; L-2-amino-3-ureidopropionic acid; L-citrulline; Lys(Me)₂-OH; Lys(N₃)—OH; Nδ-benzyloxycarbonyl-L-ornithine; Nω-nitro-D-arginine; Nω-nitro-L-arginine; α-methyl-ornithine; 2,6-diaminoheptanedioic acid; L-ornithine; (Nδ-1-(4,4-dimethyl-2,6-dioxo-cyclohex-1-ylidene)ethyl)-D-omithine; (Nδ-1-(4,4-dimethyl-2,6-dioxo-cyclohex-1-ylidene)ethyl)-L-ornithine; (Nδ-4-methyltrityl)-D-omithine; (Nδ-4-methyltrityl)-L-ornithine; D-ornithine; L-omithine; Arg(Me)(Pbf)-OH; Arg(Me)₂-OH (asymmetrical); Arg(Me)2-OH (symmetrical); Lys(ivDde)-OH; Lys(Me)2-OH.HCl; Lys(Me3)-OH chloride; Nω-nitro-D-arginine; and Nω-nitro-L-arginine.

Amino acid analogs include analogs of aspartic or glutamic acids. Examples of amino acid analogs of aspartic and glutamic acids include, but are not limited to, the following: α-methyl-D-aspartic acid; α-methyl-glutamic acid; α-methyl-L-aspartic acid; γ-methylene-glutamic acid; (N-γ-ethyl)-L-glutamine; [N-α-(4-aminobenzoyl)]-L-glutamic acid; 2,6-diaminopimelic acid; L-α-aminosuberic acid; D-2-aminoadipic acid; D-α-aminosuberic acid; α-aminopimelic acid; iminodiacetic acid; L-2-aminoadipic acid; threo-β-methyl-aspartic acid; γ-carboxy-D-glutamic acid γ,γ-di-t-butyl ester; γ-carboxy-L-glutamic acid γ,γ-di-t-butyl ester; Glu(OAll)-OH; L-Asu(OtBu)-OH; and pyroglutamic acid.

Amino acid analogs include analogs of cysteine and methionine. Examples of amino acid analogs of cysteine and methionine include, but are not limited to, Cys(farnesyl)-OH, Cys(farnesyl)-OMe, α-methyl-methionine, Cys(2-hydroxyethyl)-OH, Cys(3-aminopropyl)-OH, 2-amino-4-(ethylthio)butyric acid, buthionine, buthioninesulfoximine, ethionine, methionine methylsulfonium chloride, selenomethionine, cysteic acid, [2-(4-pyridyl)ethyl]-DL-penicillamine, [2-(4-pyridyl)ethyl]-L-cysteine, 4-methoxybenzyl-D-penicillamine, 4-methoxybenzyl-L-penicillamine, 4-methylbenzyl-D-penicillamine, 4-methylbenzyl-L-penicillamine, benzyl-D-cysteine, benzyl-L-cysteine, benzyl-DL-homocysteine, carbamoyl-L-cysteine, carboxyethyl-L-cysteine, carboxymethyl-L-cysteine, diphenylmethyl-L-cysteine, ethyl-L-cysteine, methyl-L-cysteine, t-butyl-D-cysteine, trityl-L-homocysteine, trityl-D-penicillamine, cystathionine, homocystine, L-homocystine, (2-aminoethyl)-L-cysteine, seleno-L-cystine, cystathionine, Cys(StBu)-OH, and acetamidomethyl-D-penicillamine.

Amino acid analogs include analogs of phenylalanine and tyrosine. Examples of amino acid analogs of phenylalanine and tyrosine include β-methyl-phenylalanine, β-hydroxyphenylalanine, α-methyl-3-methoxy-DL-phenylalanine, α-methyl-D-phenylalanine, α-methyl-L-phenylalanine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2,4-dichloro-phenylalanine, 2-(trifluoromethyl)-D-phenylalanine, 2-(trifluoromethyl)-L-phenylalanine, 2-bromo-D-phenylalanine, 2-bromo-L-phenylalanine, 2-chloro-D-phenylalanine, 2-chloro-L-phenylalanine, 2-cyano-D-phenylalanine, 2-cyano-L-phenylalanine, 2-fluoro-D-phenylalanine, 2-fluoro-L-phenylalanine, 2-methyl-D-phenylalanine, 2-methyl-L-phenylalanine, 2-nitro-D-phenylalanine, 2-nitro-L-phenylalanine, 2;4;5-trihydroxy-phenylalanine, 3,4,5-trifluoro-D-phenylalanine, 3,4,5-trifluoro-L-phenylalanine, 3,4-dichloro-D-phenylalanine, 3,4-dichloro-L-phenylalanine, 3,4-difluoro-D-phenylalanine, 3,4-difluoro-L-phenylalanine, 3,4-dihydroxy-L-phenylalanine, 3,4-dimethoxy-L-phenylalanine, 3,5,3′-triiodo-L-thyronine, 3,5-diiodo-D-tyrosine, 3,5-diiodo-L-tyrosine, 3,5-diiodo-L-thyronine, 3-(trifluoromethyl)-D-phenylalanine, 3-(trifluoromethyl)-L-phenylalanine, 3-amino-L-tyrosine, 3-bromo-D-phenylalanine, 3-bromo-L-phenylalanine, 3-chloro-D-phenylalanine, 3-chloro-L-phenylalanine, 3-chloro-L-tyrosine, 3-cyano-D-phenylalanine, 3-cyano-L-phenylalanine, 3-fluoro-D-phenylalanine, 3-fluoro-L-phenylalanine, 3-fluoro-tyrosine, 3-iodo-D-phenylalanine, 3-iodo-L-phenylalanine, 3-iodo-L-tyrosine, 3-methoxy-L-tyrosine, 3-methyl-D-phenylalanine, 3-methyl-L-phenylalanine, 3-nitro-D-phenylalanine, 3-nitro-L-phenylalanine, 3-nitro-L-tyrosine, 4-(trifluoromethyl)-D-phenylalanine, 4-(trifluoromethyl)-L-phenylalanine, 4-amino-D-phenylalanine, 4-amino-L-phenylalanine, 4-benzoyl-D-phenylalanine, 4-benzoyl-L-phenylalanine, 4-bis(2-chloroethyl)amino-L-phenylalanine, 4-bromo-D-phenylalanine, 4-bromo-L-phenylalanine, 4-chloro-D-phenylalanine, 4-chloro-L-phenylalanine, 4-cyano-D-phenylalanine, 4-cyano-L-phenylalanine, 4-fluoro-D-phenylalanine, 4-fluoro-L-phenylalanine, 4-iodo-D-phenylalanine, 4-iodo-L-phenylalanine, homophenylalanine, thyroxine, 3,3-diphenylalanine, thyronine, ethyl-tyrosine, and methyl-tyrosine.

Amino acid analogs include analogs of proline. Examples of amino acid analogs of proline include, but are not limited to, 3,4-dehydro-proline, 4-fluoro-proline, cis-4-hydroxy-proline, thiazolidine-2-carboxylic acid, and trans-4-fluoro-proline.

Amino acid analogs include analogs of serine and threonine. Examples of amino acid analogs of serine and threonine include, but are not limited to, 3-amino-2-hydroxy-5-methylhexanoic acid, 2-amino-3-hydroxy-4-methylpentanoic acid, 2-amino-3-ethoxybutanoic acid, 2-amino-3-methoxybutanoic acid, 4-amino-3-hydroxy-6-methylheptanoic acid, 2-amino-3-benzyloxypropionic acid, 2-amino-3-benzyloxypropionic acid, 2-amino-3-ethoxypropionic acid, 4-amino-3-hydroxybutanoic acid, and α-methylserine.

Amino acid analogs include analogs of tryptophan. Examples of amino acid analogs of tryptophan include, but are not limited to, the following: α-methyl-tryptophan; β-(3-benzothienyl)-D-alanine; β-(3-benzothienyl)-L-alanine; 1-methyl-tryptophan; 4-methyl-tryptophan; 5-benzyloxy-tryptophan; 5-bromo-tryptophan; 5-chloro-tryptophan; 5-fluoro-tryptophan; 5-hydroxy-tryptophan; 5-hydroxy-L-tryptophan; 5-methoxy-tryptophan; 5-methoxy-L-tryptophan; 5-methyl-tryptophan; 6-bromo-tryptophan; 6-chloro-D-tryptophan; 6-chloro-tryptophan; 6-fluoro-tryptophan; 6-methyl-tryptophan; 7-benzyloxy-tryptophan; 7-bromo-tryptophan; 7-methyl-tryptophan; D-1,2,3,4-tetrahydro-norharman-3-carboxylic acid; 6-methoxy-1,2,3,4-tetrahydronorharman-1-carboxylic acid; 7-azatryptophan; L-1,2,3,4-tetrahydro-norharman-3-carboxylic acid; 5-methoxy-2-methyl-tryptophan; and 6-chloro-L-tryptophan.

In some embodiments, amino acid analogs are racemic. In some embodiments, the D isomer of the amino acid analog is used. In some embodiments, the L isomer of the amino acid analog is used. In other embodiments, the amino acid analog comprises chiral centers that are in the R or S configuration. In still other embodiments, the amino group(s) of a β-amino acid analog is substituted with a protecting group, e.g., tert-butyloxycarbonyl (BOC group), 9-fluorenylmethyloxycarbonyl (FMOC), tosyl, and the like. In yet other embodiments, the carboxylic acid functional group of a β-amino acid analog is protected, e.g., as its ester derivative. In some embodiments the salt of the amino acid analog is used.

A “non-essential” amino acid residue is a residue that can be altered from the wild-type sequence of a polypeptide without abolishing or substantially altering its essential biological or biochemical activity (e.g., receptor binding or activation). An “essential” amino acid residue is a residue that, when altered from the wild-type sequence of the polypeptide, results in abolishing or substantially abolishing the polypeptide's essential biological or biochemical activity.

A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., K, R, H), acidic side chains (e.g., D, E), uncharged polar side chains (e.g., G, N, Q, S, T, Y, C), nonpolar side chains (e.g., A, V, L, I, P, F, M, W), beta-branched side chains (e.g., T, V, I) and aromatic side chains (e.g., Y, F, W, H). Thus, a predicted nonessential amino acid residue in a polypeptide, for example, is replaced with another amino acid residue from the same side chain family. Other examples of acceptable substitutions are substitutions based on isosteric considerations (e.g. norleucine for methionine) or other properties (e.g. 2-thienylalanine for phenylalanine, or 6-Cl-tryptophan for tryptophan).

The term “capping group” refers to the chemical moiety occurring at either the carboxy or amino terminus of the polypeptide chain of the subject peptidomimetic macrocycle. The capping group of a carboxy terminus includes an unmodified carboxylic acid (ie —COOH) or a carboxylic acid with a substituent. For example, the carboxy terminus can be substituted with an amino group to yield a carboxamide at the C-terminus. Various substituents include but are not limited to primary and secondary amines, including pegylated secondary amines. Representative secondary amine capping groups for the C-terminus include:

embedded image

The capping group of an amino terminus includes an unmodified amine (ie —NH₂) or an amine with a substituent. For example, the amino terminus can be substituted with an acyl group to yield a carboxamide at the N-terminus. Various substituents include but are not limited to substituted acyl groups, including C₁-C₆carbonyls, C₇-C₃₀carbonyls, and pegylated carbamates. Representative capping groups for the N-terminus include, but are not limited to, 4-FBzl (4-fluoro-benzyl) and the following:

embedded image

The term “member” as used herein in conjunction with macrocycles or macrocycle-forming linkers refers to the atoms that form or can form the macrocycle, and excludes substituent or side chain atoms. By analogy, cyclodecane, 1,2-difluoro-decane and 1,3-dimethyl cyclodecane are all considered ten-membered macrocycles as the hydrogen or fluoro substituents or methyl side chains do not participate in forming the macrocycle.

The symbol custom character when used as part of a molecular structure refers to a single bond or a trans or cis double bond.

The term “amino acid side chain” refers to a moiety attached to the α-carbon (or another backbone atom) in an amino acid. For example, the amino acid side chain for alanine is methyl, the amino acid side chain for phenylalanine is phenylmethyl, the amino acid side chain for cysteine is thiomethyl, the amino acid side chain for aspartate is carboxymethyl, the amino acid side chain for tyrosine is 4-hydroxyphenylmethyl, etc. Other non-naturally occurring amino acid side chains are also included, for example, those that occur in nature (e.g., an amino acid metabolite) or those that are made synthetically (e.g., an α,α di-substituted amino acid).

The term “α,α di-substituted amino” acid refers to a molecule or moiety containing both an amino group and a carboxyl group bound to a carbon (the α-carbon) that is attached to two natural or non-natural amino acid side chains.

The term “polypeptide” encompasses two or more naturally or non-naturally-occurring amino acids joined by a covalent bond (e.g., an amide bond). Polypeptides as described herein include full length proteins (e.g., fully processed proteins) as well as shorter amino acid sequences (e.g., fragments of naturally-occurring proteins or synthetic polypeptide fragments).

The term “first C-terminal amino acid” refers to the amino acid which is closest to the C-terminus. The term “second C-terminal amino acid” refers to the amino acid attached at the N-terminus of the first C-terminal amino acid.

The term “macrocyclization reagent” or “macrocycle-forming reagent” as used herein refers to any reagent which can be used to prepare a peptidomimetic macrocycle by mediating the reaction between two reactive groups. Reactive groups can be, for example, an azide and alkyne, in which case macrocyclization reagents include, without limitation, Cu reagents such as reagents which provide a reactive Cu(I) species, such as CuBr, CuO or CuOTf, as well as Cu(II) salts such as Cu(CO₂CH₃)₂, CuSO₄, and CuCl₂that can be converted in situ to an active Cu(I) reagent by the addition of a reducing agent such as ascorbic acid or sodium ascorbate. Macrocyclization reagents can additionally include, for example, Ru reagents known in the art such as Cp*RuCl(PPh₃)₂, [Cp*RuCl]₄or other Ru reagents which can provide a reactive Ru(II) species. In other cases, the reactive groups are terminal olefins. In such embodiments, the macrocyclization reagents or macrocycle-forming reagents are metathesis catalysts including, but not limited to, stabilized, late transition metal carbene complex catalysts such as Group VIII transition metal carbene catalysts. For example, such catalysts are Ru and Os metal centers having a +2 oxidation state, an electron count of 16 and pentacoordinated. In other examples, catalysts have W or Mo centers. Various catalysts are disclosed in Grubbs et al., “Ring Closing Metathesis and Related Processes in Organic Synthesis” Acc. Chem. Res. 1995, 28, 446-452, U.S. Pat. No. 5,811,515; U.S. Pat. No. 7,932,397; U.S. Application No. 2011/0065915; U.S. Application No. 2011/0245477; Yu et al., “Synthesis of Macrocyclic Natural Products by Catalyst-Controlled Stereoselective Ring-Closing Metathesis,” Nature 2011, 479, 88; and Peryshkov et al., “Z-Selective Olefin Metathesis Reactions Promoted by Tungsten Oxo Alkylidene Complexes,” J. Am. Chem. Soc. 2011, 133, 20754. In yet other cases, the reactive groups are thiol groups. In such embodiments, the macrocyclization reagent is, for example, a linker functionalized with two thiol-reactive groups such as halogen groups.

The term “halo” or “halogen” refers to fluorine, chlorine, bromine or iodine or a radical thereof.

The term “alkyl” refers to a hydrocarbon chain that is a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C₁-C₁₀indicates that the group has from 1 to 10 (inclusive) carbon atoms in it. In the absence of any numerical designation, “alkyl” is a chain (straight or branched) having 1 to 20 (inclusive) carbon atoms in it.

The term “alkylene” refers to a divalent alkyl (i.e., —R—).

The term “alkenyl” refers to a hydrocarbon chain that is a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C₂-C₁₀indicates that the group has from 2 to 10 (inclusive) carbon atoms in it. The term “lower alkenyl” refers to a C₂-C₆alkenyl chain. In the absence of any numerical designation, “alkenyl” is a chain (straight or branched) having 2 to 20 (inclusive) carbon atoms in it.

The term “alkynyl” refers to a hydrocarbon chain that is a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C₂-C₁₀indicates that the group has from 2 to 10 (inclusive) carbon atoms in it. The term “lower alkynyl” refers to a C₂-C₆alkynyl chain. In the absence of any numerical designation, “alkynyl” is a chain (straight or branched) having 2 to 20 (inclusive) carbon atoms in it.

The term “aryl” refers to a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atoms of each ring are substituted by a substituent. Examples of aryl groups include phenyl, naphthyl and the like. The term “arylalkoxy” refers to an alkoxy substituted with aryl.

“Arylalkyl” refers to an aryl group, as defined above, wherein one of the aryl group's hydrogen atoms has been replaced with a C₁-C₅alkyl group, as defined above. Representative examples of an arylalkyl group include, but are not limited to, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-propylphenyl, 3-propylphenyl, 4-propylphenyl, 2-butylphenyl, 3-butylphenyl, 4-butylphenyl, 2-pentylphenyl, 3-pentylphenyl, 4-pentylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2-isobutylphenyl, 3-isobutylphenyl, 4-isobutylphenyl, 2-sec-butylphenyl, 3-sec-butylphenyl, 4-sec-butylphenyl, 2-t-butylphenyl, 3-t-butylphenyl and 4-t-butylphenyl.

“Arylamido” refers to an aryl group, as defined above, wherein one of the aryl group's hydrogen atoms has been replaced with one or more —C(O)NH₂groups. Representative examples of an arylamido group include 2-C(O)NH2-phenyl, 3-C(O)NH₂-phenyl, 4-C(O)NH₂-phenyl, 2-C(O)NH₂-pyridyl, 3-C(O)NH₂-pyridyl, and 4-C(O)NH₂-pyridyl,

“Alkylheterocycle” refers to a C₁-C₅alkyl group, as defined above, wherein one of the C₁-C₅alkyl group's hydrogen atoms has been replaced with a heterocycle. Representative examples of an alkylheterocycle group include, but are not limited to, —CH₂CH₂-morpholine, —CH₂CH₂-piperidine, —CH₂CH₂CH₂-morpholine, and —CH₂CH₂CH₂-imidazole.

“Alkylamido” refers to a C₁-C₅alkyl group, as defined above, wherein one of the C₁-C₅alkyl group's hydrogen atoms has been replaced with a —C(O)NH₂group. Representative examples of an alkylamido group include, but are not limited to, —CH₂—C(O)NH₂, —CH₂CH₂—C(O)NH₂, —CH₂CH₂CH₂C(O)NH₂, —CH₂CH₂CH₂CH₂C(O)NH₂, —CH₂CH₂CH₂CH₂CH₂C(O)NH₂, —CH₂CH(C(O)NH₂)CH₃, —CH₂CH(C(O)NH₂)CH₂CH₃, —CH(C(O)NH₂)CH₂CH₃, —C(CH₃)₂CH₂C(O)NH₂, —CH₂—CH₂—NH—C(O)—CH₃, —CH₂—CH₂—NH—C(O)—CH₃—CH3, and —CH₂—CH₂—NH—C(O)—CH═CH₂.

“Alkanol” refers to a C₁-C₅alkyl group, as defined above, wherein one of the C₁-C₅alkyl group's hydrogen atoms has been replaced with a hydroxyl group. Representative examples of an alkanol group include, but are not limited to, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂OH, —CH₂CH(OH)CH₃, —CH₂CH(OH)CH₂CH₃, —CH(OH)CH₃and —C(CH₃)₂CH₂OH.

“Alkylcarboxy” refers to a C₁-C₅alkyl group, as defined above, wherein one of the C₁-C₅alkyl group's hydrogen atoms has been replaced with a —COOH group. Representative examples of an alkylcarboxy group include, but are not limited to, —CH₂COOH, —CH₂CH₂COOH, —CH₂CH₂CH₂COOH, —CH₂CH₂CH₂CH₂COOH, —CH₂CH(COOH)CH₃, —CH₂CH₂CH₂CH₂CH₂COOH, —CH₂CH(COOH)CH₂CH₃, —CH(COOH)CH₂CH₃and —C(CH₃)₂CH₂COOH.

The term “cycloalkyl” as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted. Some cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of O, N, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring are substituted by a substituent. Examples of heteroaryl groups include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl, and the like.

The term “heteroarylalkyl” or the term “heteroaralkyl” refers to an alkyl substituted with a heteroaryl. The term “heteroarylalkoxy” refers to an alkoxy substituted with heteroaryl.

The term “heterocyclyl” refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of O, N, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring are substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.

The term “substituent” refers to a group replacing a second atom or group such as a hydrogen atom on any molecule, compound or moiety. Suitable substituents include, without limitation, halo, hydroxy, mercapto, oxo, nitro, haloalkyl, alkyl, alkaryl, aryl, aralkyl, alkoxy, thioalkoxy, aryloxy, amino, alkoxycarbonyl, amido, carboxy, alkanesulfonyl, alkylcarbonyl, and cyano groups.

In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are included unless expressly provided otherwise. In some embodiments, the compounds disclosed herein are also represented in multiple tautomeric forms, in such instances, the compounds include all tautomeric forms of the compounds described herein (e.g., if alkylation of a ring system results in alkylation at multiple sites, the invention includes all such reaction products). All such isomeric forms of such compounds are included unless expressly provided otherwise. All crystal forms of the compounds described herein are included unless expressly provided otherwise.

As used herein, the terms “increase” and “decrease” mean, respectively, to cause a statistically significantly (i.e., p<0.1) increase or decrease of at least 5%.

As used herein, the recitation of a numerical range for a variable is intended to convey that the variable is equal to any of the values within that range. Thus, for a variable which is inherently discrete, the variable is equal to any integer value within the numerical range, including the end-points of the range. Similarly, for a variable which is inherently continuous, the variable is equal to any real value within the numerical range, including the end-points of the range. As an example, and without limitation, a variable which is described as having values between 0 and 2 takes the values 0, 1 or 2 if the variable is inherently discrete, and takes the values 0.0, 0.1, 0.01, 0.001, or any other real values ≥0 and ≤2 if the variable is inherently continuous.

As used herein, unless specifically indicated otherwise, the word “or” is used in the inclusive sense of “and/or” and not the exclusive sense of “either/or.”

The term “on average” represents the mean value derived from performing at least three independent replicates for each data point.

The term “biological activity” encompasses structural and functional properties of a macrocycle. Biological activity is, for example, structural stability, alpha-helicity, affinity for a target, resistance to proteolytic degradation, cell penetrability, intracellular stability, in vivo stability, or any combination thereof.

The term “binding affinity” refers to the strength of a binding interaction, for example between a peptidomimetic macrocycle and a target. Binding affinity can be expressed, for example, as an equilibrium dissociation constant (“K_D”), which is expressed in units which are a measure of concentration (e.g. M, mM, μM, nM etc). Numerically, binding affinity and K_Dvalues vary inversely, such that a lower binding affinity corresponds to a higher K_Dvalue, while a higher binding affinity corresponds to a lower K_Dvalue. Where high binding affinity is desirable, “improved” binding affinity refers to higher binding affinity and therefoere lower K_Dvalues.

The term “in vitro efficacy” refers to the extent to which a test compound, such as a peptidomimetic macrocycle, produces a beneficial result in an in vitro test system or assay. In vitro efficacy can be measured, for example, as an “IC₅₀” or “EC₅₀” value, which represents the concentration of the test compound which produces 50% of the maximal effect in the test system.

The term “ratio of in vitro efficacies” or “in vitro efficacy ratio” refers to the ratio of IC₅₀or EC₅₀values from a first assay (the numerator) versus a second assay (the denominator). Consequently, an improved in vitro efficacy ratio for Assay 1 versus Assay 2 refers to a lower value for the ratio expressed as IC₅₀(Assay 1)/IC₅₀(Assay 2) or alternatively as EC₅₀(Assay 1)/EC₅₀(Assay 2). This concept can also be characterized as “improved selectivity” in Assay 1 versus Assay 2, which can be due either to a decrease in the IC₅₀or EC₅₀value for Target 1 or an increase in the value for the IC₅₀or EC₅₀value for Target 2.

The details of one or more particular embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

Peptidomimetic Macrocycles

In some embodiments, a peptidomimetic macrocycle has the Formula (I):

embedded image

wherein:

each A, C, D, and E is independently an amino acid (including natural or non-natural amino acids, and amino acid analogs) and the terminal D and E independently optionally include a capping group;

B is an amino acid (including natural or non-natural amino acids, and amino acid analogs),

embedded image

[—NH-L₃-CO—], [—NH-L₃-SO₂—], or [—NH-L₃-];

R₁and R₂are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-;

R₃is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R₅;

L is a macrocycle-forming linker of the formula -L₁-L₂-;

each R₄is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each K is O, S, SO, SO₂, CO, CO₂, or CONR₃;

each R₅is independently halogen, alkyl, —OR₆, —N(R₆)₂, —SR₆, —SOR₆, —SO₂R₆, —CO₂R₆, a fluorescent moiety, a radioisotope or a therapeutic agent;

each R₆is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;

v and w are independently integers from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10;

u is an integer from 1-10, for example 1-5, 1-3 or 1-2;

x, y and z are independently integers from 0-10, for example the sum of x+y+z is 2, 3, or 6; and

n is an integer from 1-5.

In some embodiments, v and w are integers between 1-30. In some embodiments, w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10. In some embodiments, the sum of x+y+z is 3 or 6. In some embodiments, the sum of x+y+z is 3. In other embodiments, the sum of x+y+z is 6.

In some embodiments, peptidomimetic macrocycles are also provided of the formula:

embedded image

wherein:

each of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀is individually an amino acid, wherein at least three of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀are the same amino acid as the amino acid at the corresponding position of the sequence Phe₃-X₄-His₅-Tyr₆-Trp₇-Ala₈-Gln₉-Leu₁₀-X₁₁-Ser₁₂(SEQ ID NO: 8), where each X is an amino acid;

each D and E is independently an amino acid;

each L or L′ is independently a macrocycle-forming linker of the formula -L₁-L₂-;

R₃is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R₅;

each R₄is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each K is O, S, SO, SO₂, CO, CO₂, or CONR₃;

each R₅is independently halogen, alkyl, —OR₆, —N(R₆)₂, —SR₆, —SOR₆, —SO₂R₆, —CO₂R₆, a fluorescent moiety, a radioisotope or a therapeutic agent;

each R₆is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;

v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20 or 1-10;

w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and

n is an integer from 1-5.

In some embodiments of any of the Formulas described herein, at least three of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀are the same amino acid as the amino acid at the corresponding position of the sequence Phe₃-X₄-His₅-Tyr₆-Trp₇-Ala₈-Gln₉-Leu₁₀-X₁₁-Ser₁₂(SEQ ID NO: 8). In other embodiments, at least four of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀are the same amino acid as the amino acid at the corresponding position of the sequence Phe₃-X₄-His₅-Tyr₆-Trp₇-Ala₈-Gln₉-Leu₁₀-X₁₁-Ser₁₂(SEQ ID NO: 8). In other embodiments, at least five of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀are the same amino acid as the amino acid at the corresponding position of the sequence Phe₃-X₄-His₅-Tyr₆-Trp₇-Ala₈-Gln₉-Leu₁₀-X₁₁-Ser₁₂(SEQ ID NO: 8). In other embodiments, at least six of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀are the same amino acid as the amino acid at the corresponding position of the sequence Phe₃-X₄-His₅-Tyr₆-Trp₇-Ala₈-Gln₉-Leu₁₀-X₁₁-Ser₁₂(SEQ ID NO: 8). In other embodiments, at least seven of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀are the same amino acid as the amino acid at the corresponding position of the sequence Phe₃-X₄-His₅-Tyr₆-Trp₇-Ala₈-Gln₉-Leu₁₀-X₁₁-Ser₁₂(SEQ ID NO: 8).

In some embodiments, a peptidomimetic macrocycle has the Formula:

embedded image

wherein:

each D is independently an amino acid;

each E is independently an amino acid, for example an amino acid selected from Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine);

each L or L′ is independently a macrocycle-forming linker of the formula -L₁-L₂-;

R₃is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R₅;

each R₄is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each K is O, S, SO, SO₂, CO, CO₂, or CONR₃;

each R₅is independently halogen, alkyl, —OR₆, —N(R₆)₂, —SR₆, —SOR₆, —SO₂R₆, —CO₂R₆, a fluorescent moiety, a radioisotope or a therapeutic agent;

each R₆is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;

v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10;

w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and

n is an integer from 1-5.

In some embodiments of the above Formula, at least three of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀are the same amino acid as the amino acid at the corresponding position of the sequence Phe₃-X₄-Glu₅-Tyr₆-Trp₇-Ala₈-Gln₉-Leu₁₀/Cba₁₀-X₁₁-Ala₁₂(SEQ ID NO: 9). In other embodiments of the above Formula, at least four of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀are the same amino acid as the amino acid at the corresponding position of the sequence Phe₃-X₄-Glu₅-Tyr₆-Trp₇-Ala₈-Gln₉-Leu₁₀/Cba₁₀-X₁₁-Ala₁₂(SEQ ID NO: 9). In other embodiments of the above Formula, at least five of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀are the same amino acid as the amino acid at the corresponding position of the sequence Phe₃-X₄-Glu₅-Tyr₆-Trp₇-Ala₈-Gln₉-Leu₁₀/Cba₁₀-X₁₁-Ala₁₂(SEQ ID NO: 9). In other embodiments of the above Formula, at least six of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀are the same amino acid as the amino acid at the corresponding position of the sequence Phe₃-X₄-Glu₅-Tyr₆-Trp₇-Ala₈-Gln₉-Leu₁₀/Cba₁₀-X₁₁-Ala₁₂(SEQ ID NO: 9). In other embodiments of the above Formula, at least seven of Xaa₃, Xaa₅, Xaa₆, Xaa₇, Xaa₈, Xaa₉, and Xaa₁₀are the same amino acid as the amino acid at the corresponding position of the sequence Phe₃-X₄-Glu₅-Tyr₆-Trp₇-Ala₈-Gln₉-Leu₁₀/Cba₁₀-X₁₁-Ala₁₂(SEQ ID NO: 9).

In an embodiment of any of the Formulas described herein, L₁and L₂, either alone or in combination, do not form a triazole or a thioether.

In one example, at least one of R₁and R₂is alkyl, unsubstituted or substituted with halo-. In another example, both R₁and R₂are independently alkyl, unsubstituted or substituted with halo-. In some embodiments, at least one of R₁and R₂is methyl. In other embodiments, R₁and R₂are methyl.

In some embodiments, x+y+z is at least 3. In other embodiments, x+y+z is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, the sum of x+y+z is 3 or 6. In some embodiments, the sum of x+y+z is 3. In other embodiments, the sum of x+y+z is 6. Each occurrence of A, B, C, D or E in a macrocycle or macrocycle precursor is independently selected. For example, a sequence represented by the formula [A]_x, when x is 3, encompasses embodiments where the amino acids are not identical, e.g. Gln-Asp-Ala as well as embodiments where the amino acids are identical, e.g. Gln-Gln-Gln. This applies for any value of x, y, or z in the indicated ranges. Similarly, when u is greater than 1, each compound can encompass peptidomimetic macrocycles which are the same or different. For example, a compound can comprise peptidomimetic macrocycles comprising different linker lengths or chemical compositions.

In some embodiments, the peptidomimetic macrocycle comprises a secondary structure which is an α-helix and R₈is —H, allowing intrahelical hydrogen bonding. In some embodiments, at least one of A, B, C, D or E is an α,α-disubstituted amino acid. In one example, B is an α,α-disubstituted amino acid. For instance, at least one of A, B, C, D or E is 2-aminoisobutyric acid. In other embodiments, at least one of A, B, C, D or E is

embedded image

In other embodiments, the length of the macrocycle-forming linker L as measured from a first Cα to a second Cα is selected to stabilize a desired secondary peptide structure, such as an α-helix formed by residues of the peptidomimetic macrocycle including, but not necessarily limited to, those between the first Cα to a second Cα.

In one embodiment, the peptidomimetic macrocycle of Formula (I) is:

embedded image

wherein each R₁and R₂is independently independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-.

In related embodiments, the peptidomimetic macrocycle of Formula (I) is:

embedded image

wherein each R₁′ and R₂′ is independently an amino acid.

In other embodiments, the peptidomimetic macrocycle of Formula (I) is a compound of any of the formulas shown below:

embedded image

wherein “AA” represents any natural or non-natural amino acid side chain and custom character is [D]_v, [E]_was defined above, and n is an integer between 0 and 20, 50, 100, 200, 300, 400 or 500. In some embodiments, n is 0. In other embodiments, n is less than 50.

Exemplary embodiments of the macrocycle-forming linker L are shown below.

embedded image

In other embodiments, D and/or E in the compound of Formula I are further modified in order to facilitate cellular uptake. In some embodiments, lipidating or PEGylating a peptidomimetic macrocycle facilitates cellular uptake, increases bioavailability, increases blood circulation, alters pharmacokinetics, decreases immunogenicity and/or decreases the needed frequency of administration.

In other embodiments, at least one of [D] and [E] in the compound of Formula I represents a moiety comprising an additional macrocycle-forming linker such that the peptidomimetic macrocycle comprises at least two macrocycle-forming linkers. In a specific embodiment, a peptidomimetic macrocycle comprises two macrocycle-forming linkers. In an embodiment, u is 2.

In some embodiments, any of the macrocycle-forming linkers described herein can be used in any combination with any of the sequences shown in Table 1, Table 1a, Table 1b, or Table 1c and also with any of the R-substituents indicated herein.

In some embodiments, the peptidomimetic macrocycle comprises at least one α-helix motif. For example, A, B and/or C in the compound of Formula I include one or more α-helices. As a general matter, α-helices include between 3 and 4 amino acid residues per turn. In some embodiments, the α-helix of the peptidomimetic macrocycle includes 1 to 5 turns and, therefore, 3 to 20 amino acid residues. In specific embodiments, the α-helix includes 1 turn, 2 turns, 3 turns, 4 turns, or 5 turns. In some embodiments, the macrocycle-forming linker stabilizes an α-helix motif included within the peptidomimetic macrocycle. Thus, in some embodiments, the length of the macrocycle-forming linker L from a first Cα to a second Cα is selected to increase the stability of an α-helix. In some embodiments, the macrocycle-forming linker spans from 1 turn to 5 turns of the α-helix. In some embodiments, the macrocycle-forming linker spans approximately 1 turn, 2 turns, 3 turns, 4 turns, or 5 turns of the α-helix. In some embodiments, the length of the macrocycle-forming linker is approximately 5 Å to 9 Å per turn of the α-helix, or approximately 6 Å to 8 Å per turn of the α-helix. Where the macrocycle-forming linker spans approximately 1 turn of an α-helix, the length is equal to approximately 5 carbon-carbon bonds to 13 carbon-carbon bonds, approximately 7 carbon-carbon bonds to 11 carbon-carbon bonds, or approximately 9 carbon-carbon bonds. Where the macrocycle-forming linker spans approximately 2 turns of an α-helix, the length is equal to approximately 8 carbon-carbon bonds to 16 carbon-carbon bonds, approximately 10 carbon-carbon bonds to 14 carbon-carbon bonds, or approximately 12 carbon-carbon bonds. Where the macrocycle-forming linker spans approximately 3 turns of an α-helix, the length is equal to approximately 14 carbon-carbon bonds to 22 carbon-carbon bonds, approximately 16 carbon-carbon bonds to 20 carbon-carbon bonds, or approximately 18 carbon-carbon bonds. Where the macrocycle-forming linker spans approximately 4 turns of an α-helix, the length is equal to approximately 20 carbon-carbon bonds to 28 carbon-carbon bonds, approximately 22 carbon-carbon bonds to 26 carbon-carbon bonds, or approximately 24 carbon-carbon bonds. Where the macrocycle-forming linker spans approximately 5 turns of an α-helix, the length is equal to approximately 26 carbon-carbon bonds to 34 carbon-carbon bonds, approximately 28 carbon-carbon bonds to 32 carbon-carbon bonds, or approximately 30 carbon-carbon bonds. Where the macrocycle-forming linker spans approximately 1 turn of an α-helix, the linkage contains approximately 4 atoms to 12 atoms, approximately 6 atoms to 10 atoms, or approximately 8 atoms. Where the macrocycle-forming linker spans approximately 2 turns of the α-helix, the linkage contains approximately 7 atoms to 15 atoms, approximately 9 atoms to 13 atoms, or approximately 11 atoms. Where the macrocycle-forming linker spans approximately 3 turns of the α-helix, the linkage contains approximately 13 atoms to 21 atoms, approximately 15 atoms to 19 atoms, or approximately 17 atoms. Where the macrocycle-forming linker spans approximately 4 turns of the α-helix, the linkage contains approximately 19 atoms to 27 atoms, approximately 21 atoms to 25 atoms, or approximately 23 atoms. Where the macrocycle-forming linker spans approximately 5 turns of the α-helix, the linkage contains approximately 25 atoms to 33 atoms, approximately 27 atoms to 31 atoms, or approximately 29 atoms. Where the macrocycle-forming linker spans approximately 1 turn of the α-helix, the resulting macrocycle forms a ring containing approximately 17 members to 25 members, approximately 19 members to 23 members, or approximately 21 members. Where the macrocycle-forming linker spans approximately 2 turns of the α-helix, the resulting macrocycle forms a ring containing approximately 29 members to 37 members, approximately 31 members to 35 members, or approximately 33 members. Where the macrocycle-forming linker spans approximately 3 turns of the α-helix, the resulting macrocycle forms a ring containing approximately 44 members to 52 members, approximately 46 members to 50 members, or approximately 48 members. Where the macrocycle-forming linker spans approximately 4 turns of the α-helix, the resulting macrocycle forms a ring containing approximately 59 members to 67 members, approximately 61 members to 65 members, or approximately 63 members. Where the macrocycle-forming linker spans approximately 5 turns of the α-helix, the resulting macrocycle forms a ring containing approximately 74 members to 82 members, approximately 76 members to 80 members, or approximately 78 members.

In other embodiments, provided are peptidomimetic macrocycles of Formula (IV) or (IVa):

embedded image

wherein:

each A, C, D, and E is independently a natural or non-natural amino acid, and the terminal D and E independently optionally include a capping group;

B is a natural or non-natural amino acid, amino acid analog,

embedded image

[—NH-L₃-CO—], [—NH-L₃-SO₂—], or [—NH-L₃-];

R₃is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R₅;

L is a macrocycle-forming linker of the formula -L₁-L₂-;

each R₄is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each K is O, S, SO, SO₂, CO, CO₂, or CONR₃;

each R₅is independently halogen, alkyl, —OR₆, —N(R₆)₂, —SR₆, —SOR₆, —SO₂R₆, —CO₂R₆, a fluorescent moiety, a radioisotope or a therapeutic agent;

each R₆is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;

R₇is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R₅;

v and w are independently integers from 1-1000;

u is an integer from 1-10;

x, y and z are independently integers from 0-10; and

n is an integer from 1-5.

In one example, L₁and L₂, either alone or in combination, do not form a triazole or a thioether.

In some embodiments, x+y+z is at least 1. In other embodiments, x+y+z is at least 2. In other embodiments, x+y+z is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. Each occurrence of A, B, C, D or E in a macrocycle or macrocycle precursor is independently selected. For example, a sequence represented by the formula [A]_x, when x is 3, encompasses embodiments where the amino acids are not identical, e.g. Gln-Asp-Ala as well as embodiments where the amino acids are identical, e.g. Gln-Gln-Gln. This applies for any value of x, y, or z in the indicated ranges.

embedded image

Exemplary embodiments of the macrocycle-forming linker -L₁-L₂- are shown below.

embedded image

Unless otherwise stated, any compounds (including peptidomimetic macrocycles, macrocycle precursors, and other compositions) are also meant to encompass compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the described structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention.

In some embodiments, the compounds disclosed herein can contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). In other embodiments, one or more carbon atoms is replaced with a silicon atom. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are contemplated herein.

Preparation of Peptidomimetic Macrocycles

Peptidomimetic macrocycles can be prepared by any of a variety of methods known in the art. For example, any of the residues indicated by “$” or “$r8” in Table 1, Table 1a, Table 1b, or Table 1c can be substituted with a residue capable of forming a crosslinker with a second residue in the same molecule or a precursor of such a residue.

Various methods to effect formation of peptidomimetic macrocycles are known in the art. For example, the preparation of peptidomimetic macrocycles of Formula I is described in Schafmeister et al., J. Am. Chem. Soc. 122:5891-5892 (2000); Schafmeister & Verdine, J. Am. Chem. Soc. 122:5891 (2005); Walensky et al., Science 305:1466-1470 (2004); U.S. Pat. No. 7,192,713 and PCT application WO 2008/121767. The α,α-disubstituted amino acids and amino acid precursors disclosed in the cited references can be employed in synthesis of the peptidomimetic macrocycle precursor polypeptides. For example, the “S5-olefin amino acid” is (S)-α-(2′-pentenyl) alanine and the “R8 olefin amino acid” is (R)-α-(2′-octenyl) alanine. Following incorporation of such amino acids into precursor polypeptides, the terminal olefins are reacted with a metathesis catalyst, leading to the formation of the peptidomimetic macrocycle. In various embodiments, the following amino acids can be employed in the synthesis of the peptidomimetic macrocycle:

embedded image

In other embodiments, the peptidomimetic macrocyles are of Formula IV or IVa. Methods for the preparation of such macrocycles are described, for example, in U.S. Pat. No. 7,202,332.

Additional methods of forming peptidomimetic macrocycles which are envisioned as suitable include those disclosed by Mustapa, M. Firouz Mohd et al., J. Org. Chem (2003), 68, pp. 8193-8198; Yang, Bin et al. Bioorg Med. Chem. Lett. (2004), 14, pp. 1403-1406; U.S. Pat. No. 5,364,851; U.S. Pat. No. 5,446,128; U.S. Pat. No. 5,824,483; U.S. Pat. No. 6,713,280; and U.S. Pat. No. 7,202,332. In such embodiments, aminoacid precursors are used containing an additional substituent R— at the alpha position. Such aminoacids are incorporated into the macrocycle precursor at the desired positions, which can be at the positions where the crosslinker is substituted or, alternatively, elsewhere in the sequence of the macrocycle precursor. Cyclization of the precursor is then effected according to the indicated method.

Assays

The properties of peptidomimetic macrocycles are assayed, for example, by using the methods described below. In some embodiments, a peptidomimetic macrocycle has improved biological properties relative to a corresponding polypeptide lacking the substituents described herein.

Assay to Determine α-Helicity

In solution, the secondary structure of polypeptides with α-helical domains will reach a dynamic equilibrium between random coil structures and α-helical structures, often expressed as a “percent helicity”. Thus, for example, alpha-helical domains are predominantly random coils in solution, with α-helical content usually under 25%. Peptidomimetic macrocycles with optimized linkers, on the other hand, possess, for example, an alpha-helicity that is at least two-fold greater than that of a corresponding uncrosslinked polypeptide. In some embodiments, macrocycles will possess an alpha-helicity of greater than 50%. To assay the helicity of peptidomimetic macrocyles, the compounds are dissolved in an aqueous solution (e.g. 50 mM potassium phosphate solution at pH 7, or distilled H₂O, to concentrations of 25-50 μM). Circular dichroism (CD) spectra are obtained on a spectropolarimeter (e.g., Jasco J-710) using standard measurement parameters (e.g. temperature, 20° C.; wavelength, 190-260 nm; step resolution, 0.5 nm; speed, 20 nm/sec; accumulations, 10; response, 1 sec; bandwidth, 1 nm; path length, 0.1 cm). The α-helical content of each peptide is calculated by dividing the mean residue ellipticity (e.g. [Φ]222obs) by the reported value for a model helical decapeptide (Yang et al. (1986), Methods Enzymol. 130:208)).

Assay to Determine Melting Temperature (Tm).

A peptidomimetic macrocycle comprising a secondary structure such as an α-helix exhibits, for example, a higher melting temperature than a corresponding uncrosslinked polypeptide. Typically peptidomimetic macrocycles exhibit Tm of >60° C. representing a highly stable structure in aqueous solutions. To assay the effect of macrocycle formation on melting temperature, peptidomimetic macrocycles or unmodified peptides are dissolved in distilled H₂O (e.g. at a final concentration of 50 μM) and the Tm is determined by measuring the change in ellipticity over a temperature range (e.g. 4 to 95° C.) on a spectropolarimeter (e.g., Jasco J-710) using standard parameters (e.g. wavelength 222 nm; step resolution, 0.5 nm; speed, 20 nm/sec; accumulations, 10; response, 1 sec; bandwidth, 1 nm; temperature increase rate: 1° C./min; path length, 0.1 cm).

Protease Resistance Assay.

The amide bond of the peptide backbone is susceptible to hydrolysis by proteases, thereby rendering peptidic compounds vulnerable to rapid degradation in vivo. Peptide helix formation, however, typically buries the amide backbone and therefore can shield it from proteolytic cleavage. The peptidomimetic macrocycles can be subjected to in vitro trypsin proteolysis to assess for any change in degradation rate compared to a corresponding uncrosslinked polypeptide. For example, the peptidomimetic macrocycle and a corresponding uncrosslinked polypeptide are incubated with trypsin agarose and the reactions quenched at various time points by centrifugation and subsequent HPLC injection to quantitate the residual substrate by ultraviolet absorption at 280 nm. Briefly, the peptidomimetic macrocycle and peptidomimetic precursor (5 mcg) are incubated with trypsin agarose (Pierce) (S/E˜125) for 0, 10, 20, 90, and 180 minutes. Reactions are quenched by tabletop centrifugation at high speed; remaining substrate in the isolated supernatant is quantified by HPLC-based peak detection at 280 nm. The proteolytic reaction displays first order kinetics and the rate constant, k, is determined from a plot of In[S] versus time (k=−1× slope).

Ex Vivo Stability Assay.

Peptidomimetic macrocycles with optimized linkers possess, for example, an ex vivo half-life that is at least two-fold greater than that of a corresponding uncrosslinked polypeptide, and possess an ex vivo half-life of 12 hours or more. For ex vivo serum stability studies, a variety of assays can be used. For example, a peptidomimetic macrocycle and a corresponding uncrosslinked polypeptide (2 mcg) are incubated with fresh mouse, rat and/or human serum (2 mL) at 37° C. for 0, 1, 2, 4, 8, and 24 hours. To determine the level of intact compound, the following procedure can be used: The samples are extracted by transferring 100 μl of sera to 2 ml centrifuge tubes followed by the addition of 10 μL of 50% formic acid and 500 μL acetonitrile and centrifugation at 14,000 RPM for 10 min at 4±2° C. The supernatants are then transferred to fresh 2 ml tubes and evaporated on Turbovap under N₂<10 psi, 37° C. The samples are reconstituted in 100 μL of 50:50 acetonitrile:water and submitted to LC-MS/MS analysis.

In Vitro Binding Assays.

To assess the binding and affinity of peptidomimetic macrocycles and peptidomimetic precursors to acceptor proteins, a fluorescence polarization assay (FPA) issued, for example. The FPA technique measures the molecular orientation and mobility using polarized light and fluorescent tracer. When excited with polarized light, fluorescent tracers (e.g., FITC) attached to molecules with high apparent molecular weights (e.g. FITC-labeled peptides bound to a large protein) emit higher levels of polarized fluorescence due to their slower rates of rotation as compared to fluorescent tracers attached to smaller molecules (e.g. FITC—labeled peptides that are free in solution).

For example, fluoresceinated peptidomimetic macrocycles (25 nM) are incubated with the acceptor protein (25-1000 nM) in binding buffer (140 mM NaCl, 50 mM Tris-HCL, pH 7.4) for 30 minutes at room temperature. Binding activity is measured, for example, by fluorescence polarization on a luminescence spectrophotometer (e.g. Perkin-Elmer LS50B). Kd values can be determined by nonlinear regression analysis using, for example, Graphpad Prism software (GraphPad Software, Inc., San Diego, Calif.). A peptidomimetic macrocycle shows, In some embodiments, similar or lower Kd than a corresponding uncrosslinked polypeptide.

In Vitro Displacement Assays to Characterize Antagonists of Peptide-Protein Interactions.

To assess the binding and affinity of compounds that antagonize the interaction between a peptide and an acceptor protein, a fluorescence polarization assay (FPA) utilizing a fluoresceinated peptidomimetic macrocycle derived from a peptidomimetic precursor sequence is used, for example. The FPA technique measures the molecular orientation and mobility using polarized light and fluorescent tracer. When excited with polarized light, fluorescent tracers (e.g., FITC) attached to molecules with high apparent molecular weights (e.g. FITC-labeled peptides bound to a large protein) emit higher levels of polarized fluorescence due to their slower rates of rotation as compared to fluorescent tracers attached to smaller molecules (e.g. FITC-labeled peptides that are free in solution). A compound that antagonizes the interaction between the fluoresceinated peptidomimetic macrocycle and an acceptor protein will be detected in a competitive binding FPA experiment.

For example, putative antagonist compounds (1 nM to 1 mM) and a fluoresceinated peptidomimetic macrocycle (25 nM) are incubated with the acceptor protein (50 nM) in binding buffer (140 mM NaCl, 50 mM Tris-HCL, pH 7.4) for 30 minutes at room temperature. Antagonist binding activity is measured, for example, by fluorescence polarization on a luminescence spectrophotometer (e.g. Perkin-Elmer LS50B). Kd values can be determined by nonlinear regression analysis using, for example, Graphpad Prism software (GraphPad Software, Inc., San Diego, Calif.).

Any class of molecule, such as small organic molecules, peptides, oligonucleotides or proteins can be examined as putative antagonists in this assay.

Assay for Protein-Ligand Binding by Affinity Selection-Mass Spectrometry

To assess the binding and affinity of test compounds for proteins, an affinity-selection mass spectrometry assay is used, for example. Protein-ligand binding experiments are conducted according to the following representative procedure outlined for a system-wide control experiment using 1 μM peptidomimetic macrocycle plus 5 μM hMDM2. A 1 μL DMSO aliquot of a 40 μM stock solution of peptidomimetic macrocycle is dissolved in 19 μL of PBS (Phosphate-buffered saline: 50 mM, pH 7.5 Phosphate buffer containing 150 mM NaCl). The resulting solution is mixed by repeated pipetting and clarified by centrifugation at 10 000 g for 10 min. To a 4 μL aliquot of the resulting supernatant is added 4 μL of 10 μM hMDM2 in PBS. Each 8.0 μL experimental sample thus contains 40 pmol (1.5 μg) of protein at 5.0 μM concentration in PBS plus 1 μM peptidomimetic macrocycle and 2.5% DMSO. Duplicate samples thus prepared for each concentration point are incubated for 60 min at room temperature, and then chilled to 4° C. prior to size-exclusion chromatography-LC-MS analysis of 5.0 μL injections. Samples containing a target protein, protein-ligand complexes, and unbound compounds are injected onto an SEC column, where the complexes are separated from non-binding component by a rapid SEC step. The SEC column eluate is monitored using UV detectors to confirm that the early-eluting protein fraction, which elutes in the void volume of the SEC column, is well resolved from unbound components that are retained on the column. After the peak containing the protein and protein-ligand complexes elutes from the primary UV detector, it enters a sample loop where it is excised from the flow stream of the SEC stage and transferred directly to the LC-MS via a valving mechanism. The (M+3H)³⁺ ion of the peptidomimetic macrocycle is observed by ESI-MS at the expected m/z, confirming the detection of the protein-ligand complex.

Assay for Protein-Ligand Kd Titration Experiments.

To assess the binding and affinity of test compounds for proteins, a protein-ligand Kd titration experiment is performed, for example. Protein-ligand K_dtitrations experiments are conducted as follows: 2 μL DMSO aliquots of a serially diluted stock solution of titrant peptidomimetic macrocycle (5, 2.5, . . . , 0.098 mM) are prepared then dissolved in 38 μL of PBS. The resulting solutions are mixed by repeated pipetting and clarified by centrifugation at 10 000 g for 10 min. To 4.0 μL aliquots of the resulting supernatants is added 4.0 μL of 10 μM hMDM2 in PBS. Each 8.0 μL experimental sample thus contains 40 pmol (1.5 μg) of protein at 5.0 μM concentration in PBS, varying concentrations (125, 62.5, . . . , 0.24 μM) of the titrant peptide, and 2.5% DMSO. Duplicate samples thus prepared for each concentration point are incubated at room temperature for 30 min, then chilled to 4° C. prior to SEC-LC-MS analysis of 2.0 μL injections. The (M+H)¹⁺, (M+2H)²⁺, (M+3H)³⁺, and/or (M+Na)¹⁺ ion is observed by ESI-MS; extracted ion chromatograms are quantified, then fit to equations to derive the binding affinity K_das described in “A General Technique to Rank Protein-Ligand Binding Affinities and Determine Allosteric vs. Direct Binding Site Competition in Compound Mixtures.” Annis, D. A.; Nazef, N.; Chuang, C. C.; Scott, M. P.; Nash, H. M. J. Am. Chem. Soc. 2004, 126, 15495-15503; also in “ALIS: An Afinity Selection-Mass Spectrometry System for the Discovery and Characterization of Protein-Ligand Interactions” D. A. Annis, C.-C. Chuang, and N. Nazef. In Mass Spectrometry in Medicinal Chemistry. Edited by Wanner K, Höfner G: Wiley-VCH; 2007:121-184. Mannhold R, Kubinyi H, Folkers G (Series Editors): Methods and Principles in Medicinal Chemistry.

Assay for Competitive Binding Experiments by Affinity Selection-Mass Spectrometry

To determine the ability of test compounds to bind competitively to proteins, an affinity selection mass spectrometry assay is performed, for example. A mixture of ligands at 40 μM per component is prepared by combining 2 μL aliquots of 400 μM stocks of each of the three compounds with 14 μL of DMSO. Then, 1 μL aliquots of this 40 μM per component mixture are combined with 1 μL DMSO aliquots of a serially diluted stock solution of titrant peptidomimetic macrocycle (10, 5, 2.5, . . . , 0.078 mM). These 2 μL samples are dissolved in 38 μL of PBS. The resulting solutions were mixed by repeated pipetting and clarified by centrifugation at 10 000 g for 10 min. To 4.0 μL aliquots of the resulting supernatants is added 4.0 μL of 10 μM hMDM2 protein in PBS. Each 8.0 μL experimental sample thus contains 40 pmol (1.5 μg) of protein at 5.0 μM concentration in PBS plus 0.5 μM ligand, 2.5% DMSO, and varying concentrations (125, 62.5, . . . , 0.98 μM) of the titrant peptidomimetic macrocycle. Duplicate samples thus prepared for each concentration point are incubated at room temperature for 60 min, then chilled to 4° C. prior to SEC-LC-MS analysis of 2.0 μL injections. Additional details on these and other methods are provided in “A General Technique to Rank Protein-Ligand Binding Affinities and Determine Allosteric vs. Direct Binding Site Competition in Compound Mixtures.” Annis, D. A.; Nazef, N.; Chuang, C. C.; Scott, M. P.; Nash, H. M. J. Am. Chem. Soc. 2004, 126, 15495-15503; also in “ALIS: An Affinity Selection-Mass Spectrometry System for the Discovery and Characterization of Protein-Ligand Interactions” D. A. Annis, C.-C. Chuang, and N. Nazef. In Mass Spectrometry in Medicinal Chemistry. Edited by Wanner K, Höfner G: Wiley-VCH; 2007:121-184. Mannhold R, Kubinyi H, Folkers G (Series Editors): Methods and Principles in Medicinal Chemistry.

Binding Assays in Intact Cells.

It is possible to measure binding of peptides or peptidomimetic macrocycles to their natural acceptors in intact cells by immunoprecipitation experiments. For example, intact cells are incubated with fluoresceinated (FITC-labeled) compounds for 4 hrs in the absence of serum, followed by serum replacement and further incubation that ranges from 4-18 hrs. Cells are then pelleted and incubated in lysis buffer (50 mM Tris [pH 7.6], 150 mM NaCl, 1% CHAPS and protease inhibitor cocktail) for 10 minutes at 4° C. Extracts are centrifuged at 14,000 rpm for 15 minutes and supernatants collected and incubated with 10 μl goat anti-FITC antibody for 2 hrs, rotating at 4° C. followed by further 2 hrs incubation at 4° C. with protein A/G Sepharose (50 μl of 50% bead slurry). After quick centrifugation, the pellets are washed in lysis buffer containing increasing salt concentration (e.g., 150, 300, 500 mM). The beads are then re-equilibrated at 150 mM NaCl before addition of SDS-containing sample buffer and boiling. After centrifugation, the supernatants are optionally electrophoresed using 4%-12% gradient Bis-Tris gels followed by transfer into Immobilon-P membranes. After blocking, blots are optionally incubated with an antibody that detects FITC and also with one or more antibodies that detect proteins that bind to the peptidomimetic macrocycle.

Cellular Penetrability Assays.

A peptidomimetic macrocycle is, for example, more cell penetrable compared to a corresponding uncrosslinked macrocycle. Peptidomimetic macrocycles with optimized linkers possess, for example, cell penetrability that is at least two-fold greater than a corresponding uncrosslinked macrocycle, and often 20% or more of the applied peptidomimetic macrocycle will be observed to have penetrated the cell after 4 hours. To measure the cell penetrability of peptidomimetic macrocycles and corresponding uncrosslinked macrocycle, intact cells are incubated with fluorescently-labeled (e.g. fluoresceinated) peptidomimetic macrocycles or corresponding uncrosslinked macrocycle (10 μM) for 4 hrs in serum free media at 37° C., washed twice with media and incubated with trypsin (0.25%) for 10 min at 37° C. The cells are washed again and resuspended in PBS. Cellular fluorescence is analyzed, for example, by using either a FACSCalibur flow cytometer or Cellomics' KineticScan® HCS Reader.

Cellular Efficacy Assays.

The efficacy of certain peptidomimetic macrocycles is determined, for example, in cell-based killing assays using a variety of tumorigenic and non-tumorigenic cell lines and primary cells derived from human or mouse cell populations. Cell viability is monitored, for example, over 24-96 hrs of incubation with peptidomimetic macrocycles (0.5 to 50 μM) to identify those that kill at EC₅₀<10 μM. Several standard assays that measure cell viability are commercially available and are optionally used to assess the efficacy of the peptidomimetic macrocycles. In addition, assays that measure Annexin V and caspase activation are optionally used to assess whether the peptidomimetic macrocycles kill cells by activating the apoptotic machinery. For example, the Cell Titer-glo assay is used which determines cell viability as a function of intracellular ATP concentration.

In Vivo Stability Assay.

To investigate the in vivo stability of the peptidomimetic macrocycles, the compounds are, for example, administered to mice and/or rats by IV, IP, PO or inhalation routes at concentrations ranging from 0.1 to 50 mg/kg and blood specimens withdrawn at 0′, 5′, 15′, 30′, 1 hr, 4 hrs, 8 hrs and 24 hours post-injection. Levels of intact compound in 25 μL of fresh serum are then measured by LC-MS/MS as above.

In Vivo Efficacy in Animal Models.

To determine the anti-oncogenic activity of peptidomimetic macrocycles in vivo, the compounds are, for example, given alone (IP, IV, PO, by inhalation or nasal routes) or in combination with sub-optimal doses of relevant chemotherapy (e.g., cyclophosphamide, doxorubicin, etoposide). In one example, 5×10⁶RS4; 11 cells (established from the bone marrow of a patient with acute lymphoblastic leukemia) that stably express luciferase are injected by tail vein in NOD-SCID mice 3 hrs after they have been subjected to total body irradiation. If left untreated, this form of leukemia is fatal in 3 weeks in this model. The leukemia is readily monitored, for example, by injecting the mice with D-luciferin (60 mg/kg) and imaging the anesthetized animals (e.g., Xenogen In Vivo Imaging System, Caliper Life Sciences, Hopkinton, Mass.). Total body bioluminescence is quantified by integration of photonic flux (photons/sec) by Living Image Software (Caliper Life Sciences, Hopkinton, Mass.). Peptidomimetic macrocycles alone or in combination with sub-optimal doses of relevant chemotherapeutics agents are, for example, administered to leukemic mice (10 days after injection/day 1 of experiment, in bioluminescence range of 14-16) by tail vein or IP routes at doses ranging from 0.1 mg/kg to 50 mg/kg for 7 to 21 days. Optionally, the mice are imaged throughout the experiment every other day and survival monitored daily for the duration of the experiment. Expired mice are optionally subjected to necropsy at the end of the experiment. Another animal model is implantation into NOD-SCID mice of DoHH2, a cell line derived from human follicular lymphoma, that stably expresses luciferase. These in vivo tests optionally generate preliminary pharmacokinetic, pharmacodynamic and toxicology data.

Clinical Trials.

To determine the suitability of the peptidomimetic macrocycles for treatment of humans, clinical trials are performed. For example, patients diagnosed with cancer and in need of treatment can be selected and separated in treatment and one or more control groups, wherein the treatment group is administered a peptidomimetic macrocycle, while the control groups receive a placebo or a known anti-cancer drug. The treatment safety and efficacy of the peptidomimetic macrocycles can thus be evaluated by performing comparisons of the patient groups with respect to factors such as survival and quality-of-life. In this example, the patient group treated with a peptidomimetic macrocyle can show improved long-term survival compared to a patient control group treated with a placebo.

Pharmaceutical Compositions and Routes of Administration

Pharmaceutical compositions disclosed herein include peptidomimetic macrocycles and pharmaceutically acceptable derivatives or prodrugs thereof. A “pharmaceutically acceptable derivative” means any pharmaceutically acceptable salt, ester, salt of an ester, pro-drug or other derivative of a compound disclosed herein which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound disclosed herein. Particularly favored pharmaceutically acceptable derivatives are those that increase the bioavailability of the compounds when administered to a mammal (e.g., by increasing absorption into the blood of an orally administered compound) or which increases delivery of the active compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Some pharmaceutically acceptable derivatives include a chemical group which increases aqueous solubility or active transport across the gastrointestinal mucosa.

In some embodiments, peptidomimetic macrocycles are modified by covalently or non-covalently joining appropriate functional groups to enhance selective biological properties. Such modifications include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and alter rate of excretion.

Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecylsulfate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, tosylate and undecanoate. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alkyl)₄⁺ salts.

For preparing pharmaceutical compositions from the compounds disclosed herein, pharmaceutically acceptable carriers include either solid or liquid carriers. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which also acts as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton Pa.

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

Suitable solid excipients are carbohydrate or protein fillers include, but are not limited to sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents are added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

The pharmaceutical preparation can be in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

When one or more compositions disclosed herein comprise a combination of a peptidomimetic macrocycle and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. In some embodiments, the additional agents are administered separately, as part of a multiple dose regimen, from one or more compounds disclosed herein. Alternatively, those agents are part of a single dosage form, mixed together with the compounds disclosed herein in a single composition.

Methods of Use

In one aspect, provided herein are novel peptidomimetic macrocycles that are useful in competitive binding assays to identify agents which bind to the natural ligand(s) of the proteins or peptides upon which the peptidomimetic macrocycles are modeled. For example, in the p53/MDMX system, labeled peptidomimetic macrocycles based on p53 can be used in a MDMX binding assay along with small molecules that competitively bind to MDMX. Competitive binding studies allow for rapid in vitro evaluation and determination of drug candidates specific for the p53/MDMX system. Such binding studies can be performed with any of the peptidomimetic macrocycles disclosed herein and their binding partners.

Further provided are methods for the generation of antibodies against the peptidomimetic macrocycles. In some embodiments, these antibodies specifically bind both the peptidomimetic macrocycle and the precursor peptides, such as p53, to which the peptidomimetic macrocycles are related. Such antibodies, for example, disrupt the native protein-protein interaction, for example, binding between p53 and MDMX.

In other aspects, provided herein are both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with aberrant (e.g., insufficient or excessive) expression or activity of the molecules including p53, MDM2 or MDMX.

In another embodiment, a disorder is caused, at least in part, by an abnormal level of p53 or MDM2 or MDMX, (e.g., over or under expression), or by the presence of p53 or MDM2 or MDMX exhibiting abnormal activity. As such, the reduction in the level and/or activity of p53 or MDM2 or MDMX, or the enhancement of the level and/or activity of p53 or MDM2 or MDMX, by peptidomimetic macrocycles derived from p53, is used, for example, to ameliorate or reduce the adverse symptoms of the disorder.

In another aspect, provided herein are methods for treating or preventing a disease including hyperproliferative disease and inflammatory disorder by interfering with the interaction or binding between binding partners, for example, between p53 and MDM2 or p53 and MDMX. These methods comprise administering an effective amount of a compound to a warm blooded animal, including a human. In some embodiments, the administration of one or more compounds disclosed herein induces cell growth arrest or apoptosis.

As used herein, the term “treatment” is defined as the application or administration of a therapeutic agent to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient, who has a disease, a symptom of disease or a predisposition toward a disease, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disease, the symptoms of disease or the predisposition toward disease.

In some embodiments, the peptidomimetics macrocycles can be used to treat, prevent, and/or diagnose cancers and neoplastic conditions. As used herein, the terms “cancer”, “hyperproliferative” and “neoplastic” refer to cells having the capacity for autonomous growth, i.e., an abnormal state or condition characterized by rapidly proliferating cell growth. Hyperproliferative and neoplastic disease states can be categorized as pathologic, i.e., characterizing or constituting a disease state, or can be categorized as non-pathologic, i.e., a deviation from normal but not associated with a disease state. The term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness. A metastatic tumor can arise from a multitude of primary tumor types, including but not limited to those of breast, lung, liver, colon and ovarian origin. “Pathologic hyperproliferative” cells occur in disease states characterized by malignant tumor growth. Examples of non-pathologic hyperproliferative cells include proliferation of cells associated with wound repair. Examples of cellular proliferative and/or differentiative disorders include cancer, e.g., carcinoma, sarcoma, or metastatic disorders. In some embodiments, the peptidomimetics macrocycles are novel therapeutic agents for controlling breast cancer, ovarian cancer, colon cancer, lung cancer, metastasis of such cancers and the like.

Examples of cancers or neoplastic conditions include, but are not limited to, a fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, gastric cancer, esophageal cancer, rectal cancer, pancreatic cancer, ovarian cancer, prostate cancer, uterine cancer, cancer of the head and neck, skin cancer, brain cancer, squamous cell carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, testicular cancer, small cell lung carcinoma, non-small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, or Kaposi sarcoma.

In some embodiments, the cancer is head and neck cancer, melanoma, lung cancer, breast cancer, or glioma.

Examples of proliferative disorders include hematopoietic neoplastic disorders. As used herein, the term “hematopoietic neoplastic disorders” includes diseases involving hyperplastic/neoplastic cells of hematopoietic origin, e.g., arising from myeloid, lymphoid or erythroid lineages, or precursor cells thereof. The diseases can arise from poorly differentiated acute leukemias, e.g., erythroblastic leukemia and acute megakaryoblastic leukemia. Additional exemplary myeloid disorders include, but are not limited to, acute promyeloid leukemia (APML), acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) (reviewed in Vaickus (1991), Crit Rev. Oncol./Hemotol. 11:267-97); lymphoid malignancies include, but are not limited to acute lymphoblastic leukemia (ALL) which includes B-lineage ALL and T-lineage ALL, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia (HLL) and Waldenstrom's macroglobulinemia (WM). Additional forms of malignant lymphomas include, but are not limited to non-Hodgkin lymphoma and variants thereof, peripheral T cell lymphomas, adult T cell leukemia/lymphoma (ATL), cutaneous T-cell lymphoma (CTCL), large granular lymphocytic leukemia (LGF), Hodgkin's disease and Reed-Stemberg disease.

Examples of cellular proliferative and/or differentiative disorders of the breast include, but are not limited to, proliferative breast disease including, e.g., epithelial hyperplasia, sclerosing adenosis, and small duct papillomas; tumors, e.g., stromal tumors such as fibroadenoma, phyllodes tumor, and sarcomas, and epithelial tumors such as large duct papilloma; carcinoma of the breast including in situ (noninvasive) carcinoma that includes ductal carcinoma in situ (including Paget's disease) and lobular carcinoma in situ, and invasive (infiltrating) carcinoma including, but not limited to, invasive ductal carcinoma, invasive lobular carcinoma, medullary carcinoma, colloid (mucinous) carcinoma, tubular carcinoma, and invasive papillary carcinoma, and miscellaneous malignant neoplasms. Disorders in the male breast include, but are not limited to, gynecomastia and carcinoma.

Examples of cellular proliferative and/or differentiative disorders of the skin include, but are not limited to proliferative skin disease such as melanomas, including mucosal melanoma, superficial spreading melanoma, nodular melanoma, lentigo (e.g. lentigo maligna, lentigo maligna melanoma, or acral lentiginous melanoma), amelanotic melanoma, desmoplastic melanoma, melanoma with features of a Spitz nevus, melanoma with small nevus-like cells, polypoid melanoma, and soft-tissue melanoma; basal cell carcinomas including micronodular basal cell carcinoma, superficial basal cell carcinoma, nodular basal cell carcinoma (rodent ulcer), cystic basal cell carcinoma, cicatricial basal cell carcinoma, pigmented basal cell carcinoma, aberrant basal cell carcinoma, infiltrative basal cell carcinoma, nevoid basal cell carcinoma syndrome, polypoid basal cell carcinoma, pore-like basal cell carcinoma, and fibroepithelioma of Pinkus; squamus cell carcinomas including acanthoma (large cell acanthoma), adenoid squamous cell carcinoma, basaloid squamous cell carcinoma, clear cell squamous cell carcinoma, signet-ring cell squamous cell carcinoma, spindle cell squamous cell carcinoma, Marjolin's ulcer, erythroplasia of Queyrat, and Bowen's disease; or other skin or subcutaneous tumors.

Examples of cellular proliferative and/or differentiative disorders of the lung include, but are not limited to, bronchogenic carcinoma, including paraneoplastic syndromes, bronchioloalveolar carcinoma, neuroendocrine tumors, such as bronchial carcinoid, miscellaneous tumors, and metastatic tumors; pathologies of the pleura, including inflammatory pleural effusions, noninflammatory pleural effusions, pneumothorax, and pleural tumors, including solitary fibrous tumors (pleural fibroma) and malignant mesothelioma.

Examples of cellular proliferative and/or differentiative disorders of the colon include, but are not limited to, non-neoplastic polyps, adenomas, familial syndromes, colorectal carcinogenesis, colorectal carcinoma, and carcinoid tumors.

Examples of cellular proliferative and/or differentiative disorders of the liver include, but are not limited to, nodular hyperplasias, adenomas, and malignant tumors, including primary carcinoma of the liver and metastatic tumors.

Examples of cellular proliferative and/or differentiative disorders of the ovary include, but are not limited to, ovarian tumors such as, tumors of coelomic epithelium, serous tumors, mucinous tumors, endometrioid tumors, clear cell adenocarcinoma, cystadenofibroma, Brenner tumor, surface epithelial tumors; germ cell tumors such as mature (benign) teratomas, monodermal teratomas, immature malignant teratomas, dysgerminoma, endodermal sinus tumor, choriocarcinoma; sex cord-stomal tumors such as, granulosa-theca cell tumors, thecomafibromas, androblastomas, hill cell tumors, and gonadoblastoma; and metastatic tumors such as Krukenberg tumors.

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments described herein can be employed in practicing the invention. It is intended that the following claims define the scope and that methods and structures within the scope of these claims and their equivalents be covered thereby.

EXAMPLES
Example 1: Synthesis of 6-chlorotryptophan Fmoc Amino Acids

embedded image

Tert-butyl 6-chloro-3-formyl-1H-indole-1-carboxylate, 1. To a stirred solution of dry DMF (12 mL) was added dropwise POCl₃(3.92 mL, 43 mmol, 1.3 equiv) at 0° C. under Argon. The solution was stirred at the same temperature for 20 min before a solution of 6-chloroindole (5.0 g, 33 mmol, 1 eq.) in dry DMF (30 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred for an additional 2.5 h. Water (50 mL) was added and the solution was neutralized with 4M aqueous NaOH (pH˜8). The resulting solid was filtered off, washed with water and dried under vacuum. This material was directly used in the next step without additional purification. To a stirred solution of the crude formyl indole (33 mmol, 1 eq.) in THF (150 mL) was added successively Boc₂O (7.91 g, 36.3 mmol, 1.1 equiv) and DMAP (0.4 g, 3.3 mmol, 0.1 equiv) at room temperature under N₂. The resulting mixture was stirred at room temperature for 1.5 h and the solvent was evaporated under reduced pressure. The residue was taken up in EtOAc and washed with 1N HCl, dried and concentrated to give the formyl indole 1 (9 g, 98% over 2 steps) as a white solid. ¹H NMR (CDCl₃) δ 1.70 (s, Boc, 9H); 7.35 (dd, 1H); 8.21 (m, 3H); 10.07 (s, 1H).

Tert-butyl 6-chloro-3-(hydroxymethyl)-1H-indole-1-carboxylate, 2. To a solution of compound 1 (8.86 g, 32 mmol, 1 eq.) in ethanol (150 mL) was added NaBH₄(2.4 g, 63 mmol, 2 eq.). The reaction was stirred for 3 h at room temperature. The reaction mixture was concentrated and the residue was poured into diethyl ether and water. The organic layer was separated, dried over magnesium sulfate and concentrated to give a white solid (8.7 g, 98%). This material was directly used in the next step without additional purification. ¹H NMR (CDCl₃) δ: 1.65 (s, Boc, 9H); 4.80 (s, 2H, CH₂); 7.21 (dd, 1H); 7.53 (m, 2H); 8.16 (bs, 1H).

Tert-butyl 3-(bromomethyl)-6-chloro-1H-indole-1-carboxylate, 3. To a solution of compound 2 (4.1 g, 14.6 mmol, 1 eq.) in dichloromethane (50 mL) under argon was added a solution of triphenylphosphine (4.59 g, 17.5 mmol, 1.2 eq.) in dichloromethane (50 mL) at −40° C. The reaction solution was stirred an additional 30 min at 40° C. Then NBS (3.38 g, 19 mmol, 1.3 eq.) was added. The resulting mixture was allowed to warm to room temperature and stirred overnight. Dichloromethane was evaporated, Carbon Tetrachloride (100 mL) was added and the mixture was stirred for 1 h and filtrated. The filtrate was concentrated, loaded in a silica plug and quickly eluted with 25% EtOAc in Hexanes. The solution was concentrated to give a white foam (3.84 g, 77%). ¹H NMR (CDCl₃) δ 1.66 (s, Boc, 9H); 4.63 (s, 2H, CH₂); 7.28 (dd, 1H); 7.57 (d, 1H); 7.64 (bs, 1H); 8.18 (bs, 1H).

αMe-6Cl-Trp(Boc)-Ni-S-BPB, 4. To S-Ala-Ni-S-BPB (2.66 g, 5.2 mmol, 1 eq.) and KO-tBu (0.87 g, 7.8 mmol, 1.5 eq.) was added 50 mL of DMF under argon. The bromide derivative compound 3 (2.68 g, 7.8 mmol, 1.5 eq.) in solution of DMF (5.0 mL) was added via syringe. The reaction mixture was stirred at ambient temperature for 1 h. The solution was then quenched with 5% aqueous acetic acid and diluted with water. The desired product was extracted in dichloromethane, dried and concentrated. The oily product 4 was purified by flash chromatography (solid loading) on normal phase using EtOAc and Hexanes as eluents to give a red solid (1.78 g, 45% yield). αMe-6Cl-Trp(Boc)-Ni-S-BPB, 4: M+H calc. 775.21, M+H obs. 775.26; ¹H NMR (CDCl₃) δ: 1.23 (s, 3H, αMe); 1.56 (m, 11H, Boc+CH₂); 1.82-2.20 (m, 4H, 2CH₂); 3.03 (m, 1H, CH_α);3.24 (m, 2H, CH₂); 3.57 and 4.29 (AB system, 2H, CH₂(benzyl), J=12.8 Hz); 6.62 (d, 2H); 6.98 (d, 1H); 7.14 (m, 2H); 7.23 (m, 1H); 7.32-7.36 (m, 5H); 7.50 (m, 2H); 7.67 (bs, 1H); 7.98 (d, 2H); 8.27 (m, 2H).

Fmoc-αMe-6Cl-Trp(Boc)-OH, 6. To a solution of 3N HCl/MeOH (1/3, 15 mL) at 50° C. was added a solution of compound 4 (1.75 g, 2.3 mmol, 1 eq.) in MeOH (5 ml) dropwise. The starting material disappeared within 3-4 h. The acidic solution was then cooled to 0° C. with an ice bath and quenched with an aqueous solution of Na₂CO₃(1.21 g, 11.5 mmol, 5 eq.). Methanol was removed and 8 more equivalents of Na₂CO₃(1.95 g, 18.4 mmol) were added to the suspension. The Nickel scavenging EDTA disodium salt dihydrate (1.68 g, 4.5 mmol, 2 eq.) was then added and the suspension was stirred for 2 h. A solution of Fmoc-OSu (0.84 g, 2.5 mmol, 1.1 eq.) in acetone (50 mL) was added and the reaction was stirred overnight. Afterwards, the reaction was diluted with diethyl ether and 1N HCl. The organic layer was then dried over magnesium sulfate and concentrated in vacuo. The desired product 6 was purified on normal phase using acetone and dichloromethane as eluents to give a white foam (0.9 g, 70% yield). Fmoc-αMe-6Cl-Trp(Boc)-OH, 6: M+H calc. 575.19, M+H obs. 575.37; ¹H NMR (CDCl₃) δ 1.59 (s, 9H, Boc); 1.68 (s, 3H, Me); 3.48 (bs, 2H, CH₂); 4.22 (m, 1H, CH); 4.39 (bs, 2H, CH₂); 5.47 (s, 1H, NH); 7.10 (m, 1H); 7.18 (m, 2H); 7.27 (m, 2H); 7.39 (m, 2H); 7.50 (m, 2H); 7.75 (d, 2H); 8.12 (bs, 1H).

6Cl-Trp(Boc)-Ni-S-BPB, 5. To Gly-Ni-S-BPB (4.6 g, 9.2 mmol, 1 eq.) and KO-tBu (1.14 g, 10.1 mmol, 1.1 eq.) was added 95 mL of DMF under argon. The bromide derivative compound 3 (3.5 g, 4.6 mmol, 1.1 eq.) in solution of DMF (10 mL) was added via syringe. The reaction mixture was stirred at ambient temperature for 1 h. The solution was then quenched with 5% aqueous acetic acid and diluted with water. The desired product was extracted in dichloromethane, dried and concentrated. The oily product 5 was purified by flash chromatography (solid loading) on normal phase using EtOAc and Hexanes as eluents to give a red solid (5 g, 71% yield). 6Cl-Trp(Boc)-Ni-S-BPB, 5: M+H calc. 761.20, M+H obs. 761.34; ¹H NMR (CDCl₃) δ: 1.58 (m, 11H, Boc+CH₂); 1.84 (m, 1H); 1.96 (m, 1H); 2.24 (m, 2H, CH₂); 3.00 (m, 1H, CH_α);3.22 (m, 2H, CH₂); 3.45 and 4.25 (AB system, 2H, CH₂(benzyl), J=12.8 Hz); 4.27 (m, 1H, CH_α);6.65 (d, 2H); 6.88 (d, 1H); 7.07 (m, 2H); 7.14 (m, 2H); 7.28 (m, 3H); 7.35-7.39 (m, 2H); 7.52 (m, 2H); 7.96 (d, 2H); 8.28 (m, 2H).

Fmoc-6Cl-Trp(Boc)-OH, 7. To a solution of 3N HCl/MeOH (1/3, 44 mL) at 50° C. was added a solution of compound 5 (5 g, 6.6 mmol, 1 eq.) in MeOH (10 ml) dropwise. The starting material disappeared within 3-4 h. The acidic solution was then cooled to 0° C. with an ice bath and quenched with an aqueous solution of Na₂CO₃(3.48 g, 33 mmol, 5 eq.). Methanol was removed and 8 more equivalents of Na₂CO₃(5.57 g, 52 mmol) were added to the suspension. The Nickel scavenging EDTA disodium salt dihydrate (4.89 g, 13.1 mmol, 2 eq.) and the suspension was stirred for 2 h. A solution of Fmoc-OSu (2.21 g, 6.55 mmol, 1.1 eq.) in acetone (100 mL) was added and the reaction was stirred overnight. Afterwards, the reaction was diluted with diethyl ether and 1N HCl. The organic layer was then dried over magnesium sulfate and concentrated in vacuo. The desired product 7 was purified on normal phase using acetone and dichloromethane as eluents to give a white foam (2.6 g, 69% yield). Fmoc-6Cl-Trp(Boc)-OH, 7: M+H calc. 561.17, M+H obs. 561.37; ¹H NMR (CDCl₃) δ:1.63 (s, 9H, Boc); 3.26 (m, 2H, CH₂); 4.19 (m, 1H, CH); 4.39 (m, 2H, CH₂); 4.76 (m, 1H); 5.35 (d, 1H, NH); 7.18 (m, 2H); 7.28 (m, 2H); 7.39 (m, 3H); 7.50 (m, 2H); 7.75 (d, 2H); 8.14 (bs, 1H).

Example 2: Peptidomimetic Macrocycles

Peptidomimetic macrocycles were synthesized, purified and analyzed as previously described and as described below (Schafmeister et al., J. Am. Chem. Soc. 122:5891-5892 (2000); Schafmeister & Verdine, J. Am. Chem. Soc. 122:5891 (2005); Walensky et al., Science 305:1466-1470 (2004); and U.S. Pat. No. 7,192,713). Peptidomimetic macrocycles were designed by replacing two or more naturally occurring amino acids with the corresponding synthetic amino acids. Substitutions were made at i and i+4, and i and i+7 positions. Peptide synthesis was performed either manually or on an automated peptide synthesizer (Applied Biosystems, model 433A), using solid phase conditions, rink amide AM resin (Novabiochem), and Fmoc main-chain protecting group chemistry. For the coupling of natural Fmoc-protected amino acids (Novabiochem), 10 equivalents of amino acid and a 1:1:2 molar ratio of coupling reagents HBTU/HOBt (Novabiochem)/DIEA were employed. Non-natural amino acids (4 equiv) were coupled with a 1:1:2 molar ratio of HATU (Applied Biosystems)/HOBt/DIEA. The N-termini of the synthetic peptides were acetylated, while the C-termini were amidated.

Purification of cross-linked compounds was achieved by high performance liquid chromatography (HPLC) (Varian ProStar) on a reverse phase C18 column (Varian) to yield the pure compounds. Chemical composition of the pure products was confirmed by LC/MS mass spectrometry (Micromass LCT interfaced with Agilent 1100 HPLC system) and amino acid analysis (Applied Biosystems, model 420A).

The following protocol was used in the synthesis of dialkyne-crosslinked peptidomimetic macrocycles, including SP662, SP663 and SP664. Fully protected resin-bound peptides were synthesized on a PEG-PS resin (loading 0.45 mmol/g) on a 0.2 mmol scale. Deprotection of the temporary Fmoc group was achieved by 3×10 min treatments of the resin bound peptide with 20% (v/v) piperidine in DMF. After washing with NMP (3×), dichloromethane (3×) and NMP (3×), coupling of each successive amino acid was achieved with 1×60 min incubation with the appropriate preactivated Fmoc-amino acid derivative. All protected amino acids (0.4 mmol) were dissolved in NMP and activated with HCTU (0.4 mmol) and DIEA (0.8 mmol) prior to transfer of the coupling solution to the deprotected resin-bound peptide. After coupling was completed, the resin was washed in preparation for the next deprotection/coupling cycle. Acetylation of the amino terminus was carried out in the presence of acetic anhydride/DIEA in NMP. The LC-MS analysis of a cleaved and deprotected sample obtained from an aliquot of the fully assembled resin-bound peptide was accomplished in order to verifying the completion of each coupling. In a typical example, tetrahydrofuran (4 ml) and triethylamine (2 ml) were added to the peptide resin (0.2 mmol) in a 40 ml glass vial and shaken for 10 minutes. Pd(PPh₃)₂Cl₂(0.014 g, 0.02 mmol) and copper iodide (0.008 g, 0.04 mmol) were then added and the resulting reaction mixture was mechanically shaken 16 hours while open to atmosphere. The diyne-cyclized resin-bound peptides were deprotected and cleaved from the solid support by treatment with TFA/H₂O/TIS (95/5/5 v/v) for 2.5 h at room temperature. After filtration of the resin the TFA solution was precipitated in cold diethyl ether and centrifuged to yield the desired product as a solid. The crude product was purified by preparative HPLC.

The following protocol was used in the synthesis of single alkyne-crosslinked peptidomimetic macrocycles, including SP665. Fully protected resin-bound peptides were synthesized on a Rink amide MBHA resin (loading 0.62 mmol/g) on a 0.1 mmol scale. Deprotection of the temporary Fmoc group was achieved by 2×20 min treatments of the resin bound peptide with 25% (v/v) piperidine in NMP. After extensive flow washing with NMP and dichloromethane, coupling of each successive amino acid was achieved with 1×60 min incubation with the appropriate preactivated Fmoc-amino acid derivative. All protected amino acids (1 mmol) were dissolved in NMP and activated with HCTU (1 mmol) and DIEA (1 mmol) prior to transfer of the coupling solution to the deprotected resin-bound peptide. After coupling was completed, the resin was extensively flow washed in preparation for the next deprotection/coupling cycle. Acetylation of the amino terminus was carried out in the presence of acetic anhydride/DIEA in NMP/NMM. The LC-MS analysis of a cleaved and deprotected sample obtained from an aliquot of the fully assembled resin-bound peptide was accomplished in order to verifying the completion of each coupling. In a typical example, the peptide resin (0.1 mmol) was washed with DCM. Resin was loaded into a microwave vial. The vessel was evacuated and purged with nitrogen. Molybdenumhexacarbonyl (0.01 eq, Sigma Aldrich 199959) was added. Anhydrous chlorobenzene was added to the reaction vessel. Then 2-fluorophenol (1 eq, Sigma Aldrich F12804) was added. The reaction was then loaded into the microwave and held at 130° C. for 10 minutes. Reaction may need to be pushed a subsequent time for completion. The alkyne metathesized resin-bound peptides were deprotected and cleaved from the solid support by treatment with TFA/H₂O/TIS (94/3/3 v/v) for 3 h at room temperature. After filtration of the resin the TFA solution was precipitated in cold diethyl ether and centrifuged to yield the desired product as a solid. The crude product was purified by preparative HPLC.

Table 1 shows a list of peptidomimetic macrocycles prepared.

TABLE 1

SEQ

ID
Iso-
Found
Exact
Calc
Cale
Calc

SP
Sequence
NO:
mer
Mass
Mass
(M + 1)/1
(M + 2)/2
(M + 3)/3

SP1
Ac-F$r8AYWEAc3cL$AAA-NH2
10

1456.78
729.44
1457.79
729.4
486.6

SP2
Ac-F$r8AYWEAc3cL$AAibA-NH2
11

1470.79
736.4
1471.8
736.4
491.27

SP3
Ac-LTF$r8AYWAQL$SANle-NH2
12

1715.97
859.02
1716.98
858.99
573

SP4
Ac-LTF$r8AYWAQL$SAL-NH2
13

1715.97
859.02
1716.98
858.99
573

SP5
Ac-LTF$r8AYWAQL$SAM-NH2
14

1733.92
868.48
1734.93
867.97
578.98

SP6
Ac-LTF$r8AYWAQL$SAhL-NH2
15

1729.98
865.98
1730.99
866
577.67

SP7
Ac-LTF$r8AYWAQL$SAF-NH2
16

1749.95
876.36
1750.96
875.98
584.32

SP8
Ac-LTF$r8AYWAQL$SA1-NH2
17

1715.97
859.02
1716.98
858.99
573

SP9
Ac-LTF$r8AYWAQL$SAChg-NH2
18

1741.98
871.98
1742.99
872
581.67

SP10
Ac-LTF$r8AYWAQL$SAAib-NH2
19

1687.93
845.36
1688.94
844.97
563.65

SP11
Ac-LTF$r8AYWAQL$SAA-NH2
20

1673.92
838.01
1674.93
837.97
558.98

SP12
Ac-LTF$r8AYWA$L$S$Nle-NH2
21

1767.04
884.77
1768.05
884.53
590.02

SP13
Ac-LTF$r8AYWA$L$S$A-NH2
22

1724.99
864.23
1726
863.5
576

SP14
Ac-F$r8AYWEAc3cL$AANle-NH2
23

1498.82
750.46
1499.83
750.42
500.61

SP15
Ac-F$r8AYWEAc3cL$AAL-NH2
24

1498.82
750.46
1499.83
750.42
500.61

SP16
Ac-F$r8AYWEAc3cL$AAM-NH2
25

1516.78
759.41
1517.79
759.4
506.6

SP17
Ac-F$r8AYWEAc3cL$AAhL-NH2
26

1512.84
757.49
1513.85
757.43
505.29

SP18
Ac-F$r8AYWEAc3cL$AAF-NH2
27

1532.81
767.48
1533.82
767.41
511.94

SP19
Ac-F$r8AYWEAc3cL$AA1-NH2
28

1498.82
750.39
1499.83
750.42
500.61

SP20
Ac-F$r8AYWEAc3cL$AAChg-NH2
29

1524.84
763.48
1525.85
763.43
509.29

SP21
Ac-F$r8AYWEAc3cL$AACha-NH2
30

1538.85
770.44
1539.86
770.43
513.96

SP22
Ac-F$r8AYWEAc3cL$AAAib-NH2
31

1470.79
736.84
1471.8
736.4
491.27

SP23
Ac-LTF$r8AYWAQL$AAAibV-NH2
32

1771.01
885.81
1772.02
886.51
591.34

SP24
Ac-LTF$r8AYWAQL$AAAibV-NH2
33
iso2
1771.01
886.26
1772.02
886.51
591.34

SP25
Ac-LTF$r8AYWAQL$SAibAA-NH2
34

1758.97
879.89
1759.98
880.49
587.33

SP26
Ac-LTF$r8AYWAQL$SAibAA-NH2
35
iso2
1758.97
880.34
1759.98
880.49
587.33

SP27
Ac-HLTF$r8HHWHQL$AANleNle-NH2
36

2056.15
1028.86
2057.16
1029.08
686.39

SP28
Ac-DLTF$r8HHWHQL$RRLV-NH2
37

2190.23
731.15
2191.24
1096.12
731.08

SP29
Ac-HHTF$r8HHWHQL$AAML-NH2
38

2098.08
700.43
2099.09
1050.05
700.37

SP30
Ac-F$r8HHWHQL$RRDCha-NH2
39

1917.06
959.96
1918.07
959.54
640.03

SP31
Ac-F$r8HHWHQL$HRFV-NH2
40

1876.02
938.65
1877.03
939.02
626.35

SP32
Ac-HLTF$r8HHWHQL$AAhLA-NH2
41

2028.12
677.2
2029.13
1015.07
677.05

SP33
Ac-DLTF$r8HHWHQL$RRChg1-NH2
42

2230.26
1115.89
2231.27
1116.14
744.43

SP34
Ac-DLTF$r8HHWHQL$RRChg1-NH2
43
iso2
2230.26
1115.96
2231.27
1116.14
744.43

SP35
Ac-HHTF$r8HHWHQL$AAChav-NH2
44

2106.14
1053.95
2107.15
1054.08
703.05

SP36
Ac-F$r8HHWHQL$RRDa-NH2
45

1834.99
918.3
1836
918.5
612.67

SP37
Ac-F$r8HHWHQL$HRAibG-NH2
46

1771.95
886.77
1772.96
886.98
591.66

SP38
Ac-F$r8AYWAQL$HH1NleL-NH2
47

1730.97
866.57
1731.98
866.49
578

SP39
Ac-F$r8AYWSAL$HQANle-NH2
48

1638.89
820.54
1639.9
820.45
547.3

SP40
Ac-F$r8AYWVQL$QHChg1-NH2
49

1776.01
889.44
1777.02
889.01
593.01

SP41
Ac-F$r8AYWTAL$QQNlev-NH2
50

1671.94
836.97
1672.95
836.98
558.32

SP42
Ac-F$r8AYWYQL$HAibAa-NH2
51

1686.89
844.52
1687.9
844.45
563.3

SP43
Ac-LTF$r8AYWAQL$HHLa-NH2
52

1903.05
952.27
1904.06
952.53
635.36

SP44
Ac-LTF$r8AYWAQL$HHLa-NH2
53
iso2
1903.05
952.27
1904.06
952.53
635.36

SP45
Ac-LTF$r8AYWAQL$HQNlev-NH2
54

1922.08
962.48
1923.09
962.05
641.7

SP46
Ac-LTF$r8AYWAQL$HQNlev-NH2
55
iso2
1922.08
962.4
1923.09
962.05
641.7

SP47
Ac-LTF$r8AYWAQL$QQM1-NH2
56

1945.05
973.95
1946.06
973.53
649.36

SP48
Ac-LTF$r8AYWAQL$QQM1-NH2
57
iso2
1945.05
973.88
1946.06
973.53
649.36

SP49
Ac-LTF$r8AYWAQL$HAibhLV-NH2
58

1893.09
948.31
1894.1
947.55
632.04

SP50
Ac-LTF$r8AYWAQL$AHFA-NH2
59

1871.01
937.4
1872.02
936.51
624.68

SP51
Ac-HLTF$r8HHWHQL$AANle1-NH2
60

2056.15
1028.79
2057.16
1029.08
686.39

SP52
Ac-DLTF$r8HHWHQL$RRLa-NH2
61

2162.2
721.82
2163.21
1082.11
721.74

SP53
Ac-HHTF$r8HHWHQL$AAMv-NH2
62

2084.07
1042.92
2085.08
1043.04
695.7

SP54
Ac-F$r8HHWHQL$RRDA-NH2
63

1834.99
612.74
1836
918.5
612.67

SP55
Ac-F$r8HHWHQL$HRFCha-NH2
64

1930.06
966.47
1931.07
966.04
644.36

SP56
Ac-F$r8AYWEAL$AA-NHAm
65

1443.82
1445.71
1444.83
722.92
482.28

SP57
Ac-F$r8AYWEAL$AA-NHiAm
66

1443.82
723.13
1444.83
722.92
482.28

SP58
Ac-F$r8AYWEAL$AA-NHnPr3Ph
67

1491.82
747.3
1492.83
746.92
498.28

SP59
Ac-F$r8AYWEAL$AA-NHnBu33Me
68

1457.83
1458.94
1458.84
729.92
486.95

SP60
Ac-F$r8AYWEAL$AA-NHnPr
69

1415.79
709.28
1416.8
708.9
472.94

SP61
Ac-F$r8AYWEAL$AA-NHnEt2Ch
70

1483.85
1485.77
1484.86
742.93
495.62

SP62
Ac-F$r8AYWEAL$AA-NHnEt2Cp
71

1469.83
1470.78
1470.84
735.92
490.95

SP63
Ac-F$r8AYWEAL$AA-NHHex
72

1457.83
730.19
1458.84
729.92
486.95

SP64
Ac-LTF$r8AYWAQL$AA1A-NH2
73

1771.01
885.81
1772.02
886.51
591.34

SP65
Ac-LTF$r8AYWAQL$AA1A-NH2
74
iso2
1771.01
866.8
1772.02
886.51
591.34

SP66
Ac-LTF$r8AYWAAL$AAMA-NH2
75

1731.94
867.08
1732.95
866.98
578.32

SP67
Ac-LTF$r8AYWAAL$AAMA-NH2
76
iso2
1731.94
867.28
1732.95
866.98
578.32

SP68
Ac-LTF$r8AYWAQL$AANleA-NH2
77

1771.01
867.1
1772.02
886.51
591.34

SP69
Ac-LTF$r8AYWAQL$AANleA-NH2
78
iso2
1771.01
886.89
1772.02
886.51
591.34

SP70
Ac-LTF$r8AYWAQL$AAIa-NH2
79

1771.01
886.8
1772.02
886.51
591.34

SP71
Ac-LTF$r8AYWAQL$AAIa-NH2
80
iso2
1771.01
887.09
1772.02
886.51
591.34

SP72
Ac-LTF$r8AYWAAL$AAMa-NH2
81

1731.94
867.17
1732.95
866.98
578.32

SP73
Ac-LTF$r8AYWAAL$AAMa-NH2
82
iso2
1731.94
867.37
1732.95
866.98
578.32

SP74
Ac-LTF$r8AYWAQL$AANlea-NH2
83

1771.01
887.08
1772.02
886.51
591.34

SP75
Ac-LTF$r8AYWAQL$AANlea-NH2
84
iso2
1771.01
887.08
1772.02
886.51
591.34

SP76
Ac-LTF$r8AYWAAL$AAIv-NH2
85

1742.02
872.37
1743.03
872.02
581.68

SP77
Ac-LTF$r8AYWAAL$AAIv-NH2
86
iso2
1742.02
872.74
1743.03
872.02
581.68

SP78
Ac-LTF$r8AYWAQL$AAMv-NH2
87

1817
910.02
1818.01
909.51
606.67

SP79
Ac-LTF$r8AYWAAL$AANlev-NH2
88

1742.02
872.37
1743.03
872.02
581.68

SP80
Ac-LTF$r8AYWAAL$AANlev-NH2
89
iso2
1742.02
872.28
1743.03
872.02
581.68

SP81
Ac-LTF$r8AYWAQL$AAI1-NH2
90

1813.05
907.81
1814.06
907.53
605.36

SP82
Ac-LTF$r8AYWAQL$AAI1-NH2
91
iso2
1813.05
907.81
1814.06
907.53
605.36

SP83
Ac-LTF$r8AYWAAL$AAM1-NH2
92

1773.99
887.37
1775
888
592.34

SP84
Ac-LTF$r8AYWAQL$AANle1-NH2
93

1813.05
907.61
1814.06
907.53
605.36

SP85
Ac-LTF$r8AYWAQL$AANle1-NH2
94
iso2
1813.05
907.71
1814.06
907.53
605.36

SP86
Ac-F$r8AYWEAL$AAMA-NH2
95

1575.82
789.02
1576.83
788.92
526.28

SP87
Ac-F$r8AYWEAL$AANleA-NH2
96

1557.86
780.14
1558.87
779.94
520.29

SP88
Ac-F$r8AYWEAL$AAIa-NH2
97

1557.86
780.33
1558.87
779.94
520.29

SP89
Ac-F$r8AYWEAL$AAMa-NH2
98

1575.82
789.3
1576.83
788.92
526.28

SP90
Ac-F$r8AYWEAL$AANlea-NH2
99

1557.86
779.4
1558.87
779.94
520.29

SP91
Ac-F$r8AYWEAL$AAIv-NH2
100

1585.89
794.29
1586.9
793.95
529.64

SP92
Ac-F$r8AYWEAL$AAMv-NH2
101

1603.85
803.08
1604.86
802.93
535.62

SP93
Ac-F$r8AYWEAL$AANlev-NH2
102

1585.89
793.46
1586.9
793.95
529.64

SP94
Ac-F$r8AYWEAL$AA11-NH2
103

1599.91
800.49
1600.92
800.96
534.31

SP95
Ac-F$r8AYWEAL$AAM1-NH2
104

1617.86
809.44
1618.87
809.94
540.29

SP96
Ac-F$r8AYWEAL$AANle1-NH2
105

1599.91
801.7
1600.92
800.96
534.31

SP97
Ac-F$r8AYWEAL$AANle1-NH2
106
iso2
1599.91
801.42
1600.92
800.96
534.31

SP98
Ac-LTF$r8AY6clWAQL$SAA-NH2
107

1707.88
855.72
1708.89
854.95
570.3

SP99
Ac-LTF$r8AY6clWAQL$SAA-NH2
108
iso2
1707.88
855.35
1708.89
854.95
570.3

SP100
Ac-WTF$r8FYWSQL$AVAa-NH2
109

1922.01
962.21
1923.02
962.01
641.68

SP101
Ac-WTF$r8FYWSQL$AVAa-NH2
110
iso2
1922.01
962.49
1923.02
962.01
641.68

SP102
Ac-WTF$r8VYWSQL$AVA-NH2
111

1802.98
902.72
1803.99
902.5
602

SP103
Ac-WTF$r8VYWSQL$AVA-NH2
112
iso2
1802.98
903
1803.99
902.5
602

SP104
Ac-WTF$r8FYWSQL$SAAa-NH2
113

1909.98
956.47
1910.99
956
637.67

SP105
Ac-WTF$r8FYWSQL$SAAa-NH2
114
iso2
1909.98
956.47
1910.99
956
637.67

SP106
Ac-WTF$r8VYWSQL$AVAaa-NH2
115

1945.05
974.15
1946.06
973.53
649.36

SP107
Ac-WTF$r8VYWSQL$AVAaa-NH2
116
iso2
1945.05
973.78
1946.06
973.53
649.36

SP108
Ac-LTF$r8AYWAQL$AVG-NH2
117

1671.94
837.52
1672.95
836.98
558.32

SP109
Ac-LTF$r8AYWAQL$AVG-NH2
118
iso2
1671.94
837.21
1672.95
836.98
558.32

SP110
Ac-LTF$r8AYWAQL$AVQ-NH2
119

1742.98
872.74
1743.99
872.5
582

SP111
Ac-LTF$r8AYWAQL$AVQ-NH2
120
iso2
1742.98
872.74
1743.99
872.5
582

SP112
Ac-LTF$r8AYWAQL$SAa-NH2
121

1673.92
838.23
1674.93
837.97
558.98

SP113
Ac-LTF$r8AYWAQL$SAa-NH2
122
iso2
1673.92
838.32
1674.93
837.97
558.98

SP114
Ac-LTF$r8AYWAQhL$SAA-NH2
123

1687.93
844.37
1688.94
844.97
563.65

SP115
Ac-LTF$r8AYWAQhL$SAA-NH2
124
iso2
1687.93
844.81
1688.94
844.97
563.65

SP116
Ac-LTF$r8AYWEQLStSA$-NH2
125

1826
905.27
1827.01
914.01
609.67

SP117
Ac-LTF$r8AYWAQL$SLA-NH2
126

1715.97
858.48
1716.98
858.99
573

SP118
Ac-LTF$r8AYWAQL$SLA-NH2
127
iso2
1715.97
858.87
1716.98
858.99
573

SP119
Ac-LTF$r8AYWAQL$SWA-NH2
128

1788.96

1789.97
895.49
597.33

SP120
Ac-LTF$r8AYWAQL$SWA-NH2
129
iso2
1788.96
895.28
1789.97
895.49
597.33

SP121
Ac-LTF$r8AYWAQL$SVS-NH2
130

1717.94
859.84
1718.95
859.98
573.65

SP122
Ac-LTF$r8AYWAQL$SAS-NH2
131

1689.91
845.85
1690.92
845.96
564.31

SP123
Ac-LTF$r8AYWAQL$SVG-NH2
132

1687.93
844.81
1688.94
844.97
563.65

SP124
Ac-ETF$r8VYWAQL$SAa-NH2
133

1717.91
859.76
1718.92
859.96
573.64

SP125
Ac-ETF$r8VYWAQL$SAA-NH2
134

1717.91
859.84
1718.92
859.96
573.64

SP126
Ac-ETF$r8VYWAQL$SVA-NH2
135

1745.94
873.82
1746.95
873.98
582.99

SP127
Ac-ETF$r8VYWAQL$SLA-NH2
136

1759.96
880.85
1760.97
880.99
587.66

SP128
Ac-ETF$r8VYWAQL$SWA-NH2
137

1832.95
917.34
1833.96
917.48
611.99

SP129
Ac-ETF$r8KYWAQL$SWA-NH2
138

1861.98
931.92
1862.99
932
621.67

SP130
Ac-ETF$r8VYWAQL$SVS-NH2
139

1761.93
881.89
1762.94
881.97
588.32

SP131
Ac-ETF$r8VYWAQL$SAS-NH2
140

1733.9
867.83
1734.91
867.96
578.97

SP132
Ac-ETF$r8VYWAQL$SVG-NH2
141

1731.92
866.87
1732.93
866.97
578.31

SP133
Ac-LTF$r8VYWAQL$SSa-NH2
142

1717.94
859.47
1718.95
859.98
573.65

SP134
Ac-ETF$r8VYWAQL$SSa-NH2
143

1733.9
867.83
1734.91
867.96
578.97

SP135
Ac-LTF$r8VYWAQL$SNa-NH2
144

1744.96
873.38
1745.97
873.49
582.66

SP136
Ac-ETF$r8VYWAQL$SNa-NH2
145

1760.91
881.3
1761.92
881.46
587.98

SP137
Ac-LTF$r8VYWAQL$SAa-NH2
146

1701.95
851.84
1702.96
851.98
568.32

SP138
Ac-LTF$r8VYWAQL$SVA-NH2
147

1729.98
865.53
1730.99
866
577.67

SP139
Ac-LTF$r8VYWAQL$SVA-NH2
148
iso2
1729.98
865.9
1730.99
866
577.67

5P140
Ac-LTF$r8VYWAQL$SWA-NH2
149

1816.99
909.42
1818
909.5
606.67

5P141
Ac-LTF$r8VYWAQL$SVS-NH2
150

1745.98
873.9
1746.99
874
583

5P142
Ac-LTF$r8VYWAQL$SVS-NH2
151
iso2
1745.98
873.9
1746.99
874
583

5P143
Ac-LTF$r8VYWAQL$SAS-NH2
152

1717.94
859.84
1718.95
859.98
573.65

SP144
Ac-LTF$r8VYWAQL$SAS-NH2
153
iso2
1717.94
859.91
1718.95
859.98
573.65

SP145
Ac-LTF$r8VYWAQL$SVG-NH2
154

1715.97
858.87
1716.98
858.99
573

SP146
Ac-LTF$r8VYWAQL$SVG-NH2
155
iso2
1715.97
858.87
1716.98
858.99
573

SP147
Ac-LTF$r8EYWAQCha$SAA-NH2
156

1771.96
886.85
1772.97
886.99
591.66

SP148
Ac-LTF$r8EYWAQCha$SAA-NH2
157
iso2
1771.96
886.85
1772.97
886.99
591.66

SP149
Ac-LTF$r8EYWAQCpg$SAA-NH2
158

1743.92
872.86
1744.93
872.97
582.31

SP150
Ac-LTF$r8EYWAQCpg$SAA-NH2
159
iso2
1743.92
872.86
1744.93
872.97
582.31

SP151
Ac-LTF$r8EYWAQF$SAA-NH2
160

1765.91
883.44
1766.92
883.96
589.64

SP152
Ac-LTF$r8EYWAQF$SAA-NH2
161
iso2
1765.91
883.89
1766.92
883.96
589.64

SP153
Ac-LTF$r8EYWAQCba$SAA-NH2
162

1743.92
872.42
1744.93
872.97
582.31

SP154
Ac-LTF$r8EYWAQCba$SAA-NH2
163
iso2
1743.92
873.39
1744.93
872.97
582.31

SP155
Ac-LTF3CL$r8EYWAQL$SAA-NH2
164

1765.89
883.89
1766.9
883.95
589.64

SP156
Ac-LTF3CL$r8EYWAQL$SAA-NH2
165
iso2
1765.89
883.96
1766.9
883.95
589.64

SP157
Ac-LTF34F2$r8EYWAQL$SAA-NH2
166

1767.91
884.48
1768.92
884.96
590.31

SP158
Ac-LTF34F2$r8EYWAQL$SAA-NH2
167
iso2
1767.91
884.48
1768.92
884.96
590.31

SP159
Ac-LTF34F2$r8EYWAQhL$SAA-NH2
168

1781.92
891.44
1782.93
891.97
594.98

SP160
Ac-LTF34F2$r8EYWAQhL$SAA-NH2
169
iso2
1781.92
891.88
1782.93
891.97
594.98

SP161
Ac-ETF$r8EYWAQL$SAA-NH2
170

1747.88
874.34
1748.89
874.95
583.63

SP162
Ac-LTF$r8AYWVQL$SAA-NH2
171

1701.95
851.4
1702.96
851.98
568.32

SP163
Ac-LTF$r8AHWAQL$SAA-NH2
172

1647.91
824.83
1648.92
824.96
550.31

SP164
Ac-LTF$r8AEWAQL$SAA-NH2
173

1639.9
820.39
1640.91
820.96
547.64

SP165
Ac-LTF$r8ASWAQL$SAA-NH2
174

1597.89
799.38
1598.9
799.95
533.64

SP166
Ac-LTF$r8AEWAQL$SAA-NH2
175
iso2
1639.9
820.39
1640.91
820.96
547.64

SP167
Ac-LTF$r8ASWAQL$SAA-NH2
176
iso2
1597.89
800.31
1598.9
799.95
533.64

SP168
Ac-LTF$r8AF4coohWAQL$SAA-NH2
177

1701.91
851.4
1702.92
851.96
568.31

SP169
Ac-LTF$r8AF4coohWAQL$SAA-NH2
178
iso2
1701.91
851.4
1702.92
851.96
568.31

SP170
Ac-LTF$r8AHWAQL$AAIa-NH2
179

1745
874.13
1746.01
873.51
582.67

SP171
Ac-ITF$r8FYWAQL$AAIa-NH2
180

1847.04
923.92
1848.05
924.53
616.69

SP172
Ac-ITF$r8EFIWAQL$AAIa-NH2
181

1803.01
903.17
1804.02
902.51
602.01

SP173
Ac-ITF$r8EFIWAQL$AAIa-NH2
182
iso2
1803.01
903.17
1804.02
902.51
602.01

SP174
Ac-ETF$r8EFIWAQL$AAIa-NH2
183

1818.97
910.76
1819.98
910.49
607.33

SP175
Ac-ETF$r8EFIWAQL$AAIa-NH2
184
iso2
1818.9
910.85
1819.98
910.49
607.33

SP176
Ac-LTF$r8AHWVQL$AAIa-NH2
185

1773.03
888.09
1774.04
887.52
592.02

SP177
Ac-ITF$r8FYWVQL$AAIa-NH2
186

1875.07
939.16
1876.08
938.54
626.03

SP178
Ac-ITF$r8EYWVQL$AAIa-NH2
187

1857.04
929.83
1858.05
929.53
620.02

SP179
Ac-ITF$r8EFIWVQL$AAIa-NH2
188

1831.04
916.86
1832.05
916.53
611.35

SP180
Ac-LTF$r8AEWAQL$AAIa-NH2
189

1736.99
869.87
1738
869.5
580

SP181
Ac-LTF$r8AF4coohWAQL$AAIa-NH2
190

1799
900.17
1800.01
900.51
600.67

SP182
Ac-LTF$r8AF4coohWAQL$AAIa-NH2
191
iso2
1799
900.24
1800.01
900.51
600.67

SP183
Ac-LTF$r8AHWAQL$AHFA-NH2
192

1845.01
923.89
1846.02
923.51
616.01

SP184
Ac-ITF$r8FYWAQL$AHFA-NH2
193

1947.05
975.05
1948.06
974.53
650.02

SP185
Ac-ITF$r8FYWAQL$AHFA-NH2
194
iso2
1947.05
976.07
1948.06
974.53
650.02

SP186
Ac-ITF$r8FHWAQL$AEFA-NH2
195

1913.02
958.12
1914.03
957.52
638.68

SP187
Ac-ITF$r8FHWAQL$AEFA-NH2
196
iso2
1913.02
957.86
1914.03
957.52
638.68

SP188
Ac-ITF$r8EFIWAQL$AHFA-NH2
197

1903.01
952.94
1904.02
952.51
635.34

SP189
Ac-ITF$r8EFIWAQL$AHFA-NH2
198
iso2
1903.01
953.87
1904.02
952.51
635.34

SP190
Ac-LTF$r8AHWVQL$AHFA-NH2
199

1873.04
937.86
1874.05
937.53
625.35

SP191
Ac-ITF$r8FYWVQL$AHFA-NH2
200

1975.08
988.83
1976.09
988.55
659.37

SP192
Ac-ITF$r8EYWVQL$AHFA-NH2
201

1957.05
979.35
1958.06
979.53
653.36

SP193
Ac-ITF$r8EFIWVQL$AHFA-NH2
202

1931.05
967
1932.06
966.53
644.69

SP194
Ac-ITF$r8EFIWVQL$AHFA-NH2
203
iso2
1931.05
967.93
1932.06
966.53
644.69

SP195
Ac-ETF$r8EYWAAL$SAA-NH2
204

1690.86
845.85
1691.87
846.44
564.63

SP196
Ac-LTF$r8AYWVAL$SAA-NH2
205

1644.93
824.08
1645.94
823.47
549.32

SP197
Ac-LTF$r8AHWAAL$SAA-NH2
206

1590.89
796.88
1591.9
796.45
531.3

SP198
Ac-LTF$r8AEWAAL$SAA-NH2
207

1582.88
791.9
1583.89
792.45
528.63

SP199
Ac-LTF$r8AEWAAL$SAA-NH2
208
iso2
1582.88
791.9
1583.89
792.45
528.63

SP200
Ac-LTF$r8ASWAAL$SAA-NH2
209

1540.87
770.74
1541.88
771.44
514.63

SP201
Ac-LTF$r8ASWAAL$SAA-NH2
210
iso2
1540.87
770.88
1541.88
771.44
514.63

SP202
Ac-LTF$r8AYWAAL$AAIa-NH2
211

1713.99
857.39
1715
858
572.34

SP203
Ac-LTF$r8AYWAAL$AAIa-NH2
212
iso2
1713.99
857.84
1715
858
572.34

SP204
Ac-LTF$r8AYWAAL$AHFA-NH2
213

1813.99
907.86
1815
908
605.67

SP205
Ac-LTF$r8EFIWAQL$AHIa-NH2
214

1869.03
936.1
1870.04
935.52
624.02

SP206
Ac-LTF$r8EFIWAQL$AHIa-NH2
215
iso2
1869.03
937.03
1870.04
935.52
624.02

SP207
Ac-LTF$r8AHWAQL$AHIa-NH2
216

1811.03
906.87
1812.04
906.52
604.68

SP208
Ac-LTF$r8EYWAQL$AHIa-NH2
217

1895.04
949.15
1896.05
948.53
632.69

SP209
Ac-LTF$r8AYWAQL$AAFa-NH2
218

1804.99
903.2
1806
903.5
602.67

SP210
Ac-LTF$r8AYWAQL$AAFa-NH2
219
iso2
1804.99
903.28
1806
903.5
602.67

SP211
Ac-LTF$r8AYWAQL$AAWa-NH2
220

1844
922.81
1845.01
923.01
615.67

SP212
Ac-LTF$r8AYWAQL$AAVa-NH2
221

1756.99
878.86
1758
879.5
586.67

SP213
Ac-LTF$r8AYWAQL$AAVa-NH2
222
iso2
1756.99
879.3
1758
879.5
586.67

SP214
Ac-LTF$r8AYWAQL$AALa-NH2
223

1771.01
886.26
1772.02
886.51
591.34

SP215
Ac-LTF$r8AYWAQL$AALa-NH2
224
iso2
1771.01
886.33
1772.02
886.51
591.34

SP216
Ac-LTF$r8EYWAQL$AAIa-NH2
225

1829.01
914.89
1830.02
915.51
610.68

SP217
Ac-LTF$r8EYWAQL$AAIa-NH2
226
iso2
1829.01
915.34
1830.02
915.51
610.68

SP218
Ac-LTF$r8EYWAQL$AAFa-NH2
227

1863
932.87
1864.01
932.51
622.01

SP219
Ac-LTF$r8EYWAQL$AAFa-NH2
228
iso2
1863
932.87
1864.01
932.51
622.01

SP220
Ac-LTF$r8EYWAQL$AAVa-NH2
229

1815
908.23
1816.01
908.51
606.01

SP221
Ac-LTF$r8EYWAQL$AAVa-NH2
230
iso2
1815
908.31
1816.01
908.51
606.01

SP222
Ac-LTF$r8EFIWAQL$AAIa-NH2
231

1803.01
903.17
1804.02
902.51
602.01

SP223
Ac-LTF$r8EFIWAQL$AAIa-NH2
232
iso2
1803.01
902.8
1804.02
902.51
602.01

SP224
Ac-LTF$r8EFIWAQL$AAWa-NH2
233

1876
939.34
1877.01
939.01
626.34

SP225
Ac-LTF$r8EFIWAQL$AAWa-NH2
234
iso2
1876
939.62
1877.01
939.01
626.34

SP226
Ac-LTF$r8EFIWAQL$AALa-NH2
235

1803.01
902.8
1804.02
902.51
602.01

SP227
Ac-LTF$r8EFIWAQL$AALa-NH2
236
iso2
1803.01
902.9
1804.02
902.51
602.01

SP228
Ac-ETF$r8EFIWVQL$AALa-NH2
237

1847
924.82
1848.01
924.51
616.67

SP229
Ac-LTF$r8AYWAQL$AAAa-NH2
238

1728.96
865.89
1729.97
865.49
577.33

SP230
Ac-LTF$r8AYWAQL$AAAa-NH2
239
iso2
1728.96
865.89
1729.97
865.49
577.33

SP231
Ac-LTF$r8AYWAQL$AAAibA-NH2
240

1742.98
872.83
1743.99
872.5
582

SP232
Ac-LTF$r8AYWAQL$AAAibA-NH2
241
iso2
1742.98
872.92
1743.99
872.5
582

SP233
Ac-LTF$r8AYWAQL$AAAAa-NH2
242

1800
901.42
1801.01
901.01
601.01

SP234
Ac-LTF$r5AYWAQL$s8AAIa-NH2
243

1771.01
887.17
1772.02
886.51
591.34

SP235
Ac-LTF$r5AYWAQL$s8SAA-NH2
244

1673.92
838.33
1674.93
837.97
558.98

SP236
Ac-LTF$r8AYWAQCba$AANleA-NH2
245

1783.01
892.64
1784.02
892.51
595.34

SP237
Ac-ETF$r8AYWAQCba$AANleA-NH2
246

1798.97
900.59
1799.98
900.49
600.66

SP238
Ac-LTF$r8EYWAQCba$AANleA-NH2
247

1841.01
922.05
1842.02
921.51
614.68

SP239
Ac-LTF$r8AYWAQCba$AWNleA-NH2
248

1898.05
950.46
1899.06
950.03
633.69

SP240
Ac-ETF$r8AYWAQCba$AWNleA-NH2
249

1914.01
958.11
1915.02
958.01
639.01

SP241
Ac-LTF$r8EYWAQCba$AWNleA-NH2
250

1956.06
950.62
1957.07
979.04
653.03

SP242
Ac-LTF$r8EYWAQCba$SAFA-NH2
251

1890.99
946.55
1892
946.5
631.34

SP243
Ac-LTF34F2$r8EYWAQCba$SANleA-NH2
252

1892.99
947.57
1894
947.5
632

SP244
Ac-LTF$r8EF4coohWAQCba$SANleA-NH2
253

1885
943.59
1886.01
943.51
629.34

SP245
Ac-LTF$r8EYWSQCba$SANleA-NH2
254

1873
937.58
1874.01
937.51
625.34

SP246
Ac-LTF$r8EYWWQCba$SANleA-NH2
255

1972.05
987.61
1973.06
987.03
658.36

SP247
Ac-LTF$r8EYWAQCba$AAIa-NH2
256

1841.01
922.05
1842.02
921.51
614.68

SP248
Ac-LTF34F2$r8EYWAQCba$AAIa-NH2
257

1876.99
939.99
1878
939.5
626.67

SP249
Ac-LTF$r8EF4coohWAQCba$AAIa-NH2
258

1869.01
935.64
1870.02
935.51
624.01

SP250
Pam-ETF$r8EYWAQCba$SAA-NH2
259

1956.1
979.57
1957.11
979.06
653.04

SP251
Ac-LThF$r8EFWAQCba$SAA-NH2
260

1741.94
872.11
1742.95
871.98
581.65

SP252
Ac-LTA$r8EYWAQCba$SAA-NH2
261

1667.89
835.4
1668.9
834.95
556.97

SP253
Ac-LTF$r8EYAAQCba$SAA-NH2
262

1628.88
815.61
1629.89
815.45
543.97

SP254
Ac-LTF$r8EY2Na1AQCba$SAA-NH2
263

1754.93
879.04
1755.94
878.47
585.98

SP255
Ac-LTF$r8AYWAQCba$SAA-NH2
264

1685.92
844.71
1686.93
843.97
562.98

SP256
Ac-LTF$r8EYWAQCba$SAF-NH2
265

1819.96
911.41
1820.97
910.99
607.66

SP257
Ac-LTF$r8EYWAQCba$SAFa-NH2
266

1890.99
947.41
1892
946.5
631.34

SP258
Ac-LTF$r8AYWAQCba$SAF-NH2
267

1761.95
882.73
1762.96
881.98
588.32

SP259
Ac-LTF34F2$r8AYWAQCba$SAF-NH2
268

1797.93
900.87
1798.94
899.97
600.32

SP260
Ac-LTF$r8AF4coohWAQCba$SAF-NH2
269

1789.94+
896.43
1790.95
895.98
597.65

SP261
Ac-LTF$r8EY6clWAQCba$SAF-NH2
270

1853.92
929.27
1854.93
927.97
618.98

SP262
Ac-LTF$r8AYWSQCba$SAF-NH2
271

1777.94
890.87
1778.95
889.98
593.65

SP263
Ac-LTF$r8AYWWQCba$SAF-NH2
272

1876.99
939.91
1878
939.5
626.67

SP264
Ac-LTF$r8AYWAQCba$AAIa-NH2
273

1783.01
893.19
1784.02
892.51
595.34

SP265
Ac-LTF34F2$r8AYWAQCba$AAIa-NH2
274

1818.99
911.23
1820
910.5
607.34

SP266
Ac-LTF$r8AY6clWAQCba$AAIa-NH2
275

1816.97
909.84
1817.98
909.49
606.66

SP267
Ac-LTF$r8AF4coohWAQCba$AAIa-NH2
276

1811
906.88
1812.01
906.51
604.67

SP268
Ac-LTF$r8EYWAQCba$AAFa-NH2
277

1875
938.6
1876.01
938.51
626.01

SP269
Ac-LTF$r8EYWAQCba$AAFa-NH2
278
iso2
1875
938.6
1876.01
938.51
626.01

SP270
Ac-ETF$r8AYWAQCba$AWNlea-NH2
279

1914.01
958.42
1915.02
958.01
639.01

SP271
Ac-LTF$r8EYWAQCba$AWNlea-NH2
280

1956.06
979.42
1957.07
979.04
653.03

SP272
Ac-ETF$r8EYWAQCba$AWNlea-NH2
281

1972.01
987.06
1973.02
987.01
658.34

SP273
Ac-ETF$r8EYWAQCba$AWNlea-NH2
282
iso2
1972.01
987.06
1973.02
987.01
658.34

SP274
Ac-LTF$r8AYWAQCba$SAFa-NH2
283

1832.99
917.89
1834
917.5
612

SP275
Ac-LTF$r8AYWAQCba$SAFa-NH2
284
iso2
1832.99
918.07
1834
917.5
612

SP276
Ac-ETF$r8AYWAQL$AWNlea-NH2
285

1902.01
952.22
1903.02
952.01
635.01

SP277
Ac-LTF$r8EYWAQL$AWNlea-NH2
286

1944.06
973.5
1945.07
973.04
649.03

SP278
Ac-ETF$r8EYWAQL$AWNlea-NH2
287

1960.01
981.46
1961.02
981.01
654.34

SP279
Dmaac-LTF$r8EYWAQhL$SAA-NH2
288

1788.98
896.06
1789.99
895.5
597.33

SP280
Hexac-LTF$r8EYWAQhL$SAA-NH2
289

1802
902.9
1803.01
902.01
601.67

SP281
Napac-LTF$r8EYWAQhL$SAA-NH2
290

1871.99
937.58
1873
937
625

SP282
Decac-LTF$r8EYWAQhL$SAA-NH2
291

1858.06
930.55
1859.07
930.04
620.36

SP283
Admac-LTF$r8EYWAQhL$SAA-NH2
292

1866.03
934.07
1867.04
934.02
623.02

SP284
Tmac-LTF$r8EYWAQhL$SAA-NH2
293

1787.99
895.41
1789
895
597

SP285
Pam-LTF$r8EYWAQhL$SAA-NH2
294

1942.16
972.08
1943.17
972.09
648.39

SP286
Ac-LTF$r8AYWAQCba$AANleA-NH2
295
iso2
1783.01
892.64
1784.02
892.51
595.34

SP287
Ac-LTF34F2$r8EYWAQCba$AAIa-NH2
296
iso2
1876.99
939.62
1878
939.5
626.67

SP288
Ac-LTF34F2$r8EYWAQCba$SAA-NH2
297

1779.91
892.07
1780.92
890.96
594.31

SP289
Ac-LTF34F2$r8EYWAQCba$SAA-NH2
298
iso2
1779.91
891.61
1780.92
890.96
594.31

SP290
Ac-LTF$r8EF4coohWAQCba$SAA-NH2
299

1771.92
887.54
1772.93
886.97
591.65

SP291
Ac-LTF$r8EF4coohWAQCba$SAA-NH2
300
iso2
1771.92
887.63
1772.93
886.97
591.65

SP292
Ac-LTF$r8EYWSQCba$SAA-NH2
301

1759.92
881.9
1760.93
880.97
587.65

SP293
Ac-LTF$r8EYWSQCba$SAA-NH2
302
iso2
1759.92
881.9
1760.93
880.97
587.65

SP294
Ac-LTF$r8EYWAQhL$SAA-NH2
303

1745.94
875.05
1746.95
873.98
582.99

SP295
Ac-LTF$r8AYWAQhL$SAF-NH2
304

1763.97
884.02
1764.98
882.99
589

SP296
Ac-LTF$r8AYWAQhL$SAF-NH2
305
iso2
1763.97
883.56
1764.98
882.99
589

SP297
Ac-LTF34F2$r8AYWAQhL$SAA-NH2
306

1723.92
863.67
1724.93
862.97
575.65

SP298
Ac-LTF34F2$r8AYWAQhL$SAA-NH2
307
iso2
1723.92
864.04
1724.93
862.97
575.65

SP299
Ac-LTF$r8AF4coohWAQhL$SAA-NH2
308

1715.93
859.44
1716.94
858.97
572.98

SP300
Ac-LTF$r8AF4coohWAQhL$SAA-NH2
309
iso2
1715.93
859.6
1716.94
858.97
572.98

SP301
Ac-LTF$r8AYWSQhL$SAA-NH2
310

1703.93
853.96
1704.94
852.97
568.98

SP302
Ac-LTF$r8AYWSQhL$SAA-NH2
311
iso2
1703.93
853.59
1704.94
852.97
568.98

SP303
Ac-LTF$r8EYWAQL$AANleA-NH2
312

1829.01
915.45
1830.02
915.51
610.68

SP304
Ac-LTF34F2$r8AYWAQL$AANleA-NH2
313

1806.99
904.58
1808
904.5
603.34

SP305
Ac-LTF$r8AF4coohWAQL$AANleA-NH2
314

1799
901.6
1800.01
900.51
600.67

SP306
Ac-LTF$r8AYWSQL$AANleA-NH2
315

1787
894.75
1788.01
894.51
596.67

SP307
Ac-LTF34F2$r8AYWAQhL$AANleA-NH2
316

1821
911.79
1822.01
911.51
608.01

SP308
Ac-LTF34F2$r8AYWAQhL$AANleA-NH2
317
iso2
1821
912.61
1822.01
911.51
608.01

SP309
Ac-LTF$r8AF4coohWAQhL$AANleA-NH2
318

1813.02
907.95
1814.03
907.52
605.35

SP310
Ac-LTF$r8AF4coohWAQhL$AANleA-NH2
319
iso2
1813.02
908.54
1814.03
907.52
605.35

SP311
Ac-LTF$r8AYWSQhL$AANleA-NH2
320

1801.02
901.84
1802.03
901.52
601.35

SP312
Ac-LTF$r8AYWSQhL$AANleA-NH2
321
iso2
1801.02
902.62
1802.03
901.52
601.35

SP313
Ac-LTF$r8AYWAQhL$AAAAa-NH2
322

1814.01
908.63
1815.02
908.01
605.68

SP314
Ac-LTF$r8AYWAQhL$AAAAa-NH2
323
iso2
1814.01
908.34
1815.02
908.01
605.68

SP315
Ac-LTF$r8AYWAQL$AAAAAa-NH2
324

1871.04
936.94
1872.05
936.53
624.69

SP316
Ac-LTF$r8AYWAQL$AAAAAAa-NH2
325
iso2
1942.07
972.5
1943.08
972.04
648.37

SP317
Ac-LTF$r8AYWAQL$AAAAAAa-NH2
326
iso1
1942.07
972.5
1943.08
972.04
648.37

SP318
Ac-LTF$r8EYWAQhL$AANleA-NH2
327

1843.03
922.54
1844.04
922.52
615.35

SP319
Ac-AATF$r8AYWAQL$AANleA-NH2
328

1800
901.39
1801.01
901.01
601.01

SP320
Ac-LTF$r8AYWAQL$AANleAA-NH2
329

1842.04
922.45
1843.05
922.03
615.02

SP321
Ac-ALTF$r8AYWAQL$AANleAA-NH2
330

1913.08
957.94
1914.09
957.55
638.7

SP322
Ac-LTF$r8AYWAQCba$AANleAA-NH2
331

1854.04
928.43
1855.05
928.03
619.02

SP323
Ac-LTF$r8AYWAQhL$AANleAA-NH2
332

1856.06
929.4
1857.07
929.04
619.69

SP324
Ac-LTF$r8EYWAQCba$SAAA-NH2
333

1814.96
909.37
1815.97
908.49
605.99

SP325
Ac-LTF$r8EYWAQCba$SAAA-NH2
334
iso2
1814.96
909.37
1815.97
908.49
605.99

SP326
Ac-LTF$r8EYWAQCba$SAAAA-NH2
335

1886
944.61
1887.01
944.01
629.67

SP327
Ac-LTF$r8EYWAQCba$SAAAA-NH2
336
iso2
1886
944.61
1887.01
944.01
629.67

SP328
Ac-ALTF$r8EYWAQCba$SAA-NH2
337

1814.96
909.09
1815.97
908.49
605.99

SP329
Ac-ALTF$r8EYWAQCba$SAAA-NH2
338

1886
944.61
1887.01
944.01
629.67

SP330
Ac-ALTF$r8EYWAQCba$SAA-NH2
339
iso2
1814.96
909.09
1815.97
908.49
605.99

SP331
Ac-LTF$r8EYWAQL$AAAAAa-NH2
340
iso2
1929.04
966.08
1930.05
965.53
644.02

SP332
Ac-LTF$r8EY6clWAQCba$SAA-NH2
341

1777.89
890.78
1778.9
889.95
593.64

SP333
Ac-LTF$r8EF4cooh6clWAQCba$SANleA-
342

1918.96
961.27
1919.97
960.49
640.66

NH2

SP334
Ac-LTF$r8EF4cooh6clWAQCba$SANleA-
343
iso2
1918.96
961.27
1919.97
960.49
640.66

NH2

SP335
Ac-LTF$r8EF4cooh6clWAQCba$AAIa-
344

1902.97
953.03
1903.98
952.49
635.33

NH2

SP336
Ac-LTF$r8EF4cooh6clWAQCba$AAIa-
345
iso2
1902.97
953.13
1903.98
952.49
635.33

NH2

SP337
Ac-LTF$r8AY6clWAQL$AAAAAa-NH2
346

1905
954.61
1906.01
953.51
636.01

SP338
Ac-LTF$r8AY6clWAQL$AAAAAa-NH2
347
iso2
1905
954.9
1906.01
953.51
636.01

SP339
Ac-F$r8AY6clWEAL$AAAAAAa-NH2
348

1762.89
883.01
1763.9
882.45
588.64

SP340
Ac-ETF$r8EYWAQL$AAAAAa-NH2
349

1945
974.31
1946.01
973.51
649.34

SP341
Ac-ETF$r8EYWAQL$AAAAAa-NH2
350
iso2
1945
974.49
1946.01
973.51
649.34

SP342
Ac-LTF$r8EYWAQL$AAAAAAa-NH2
351

2000.08
1001.6
2001.09
1001.05
667.7

SP343
Ac-LTF$r8EYWAQL$AAAAAAa-NH2
352
iso2
2000.08
1001.6
2001.09
1001.05
667.7

SP344
Ac-LTF$r8AYWAQL$AANleAAa-NH2
353

1913.08
958.58
1914.09
957.55
638.7

SP345
Ac-LTF$r8AYWAQL$AANleAAa-NH2
354
iso2
1913.08
958.58
1914.09
957.55
638.7

SP346
Ac-LTF$r8EYWAQCba$AAAAAa-NH2
355

1941.04
972.55
1942.05
971.53
648.02

SP347
Ac-LTF$r8EYWAQCba$AAAAAa-NH2
356
iso2
1941.04
972.55
1942.05
971.53
648.02

SP348
Ac-LTF$r8EF4coohWAQCba$AAAAAa-NH2
357

1969.04
986.33
1970.05
985.53
657.35

SP349
Ac-LTF$r8EF4coohWAQCba$AAAAAa-NH2
358
iso2
1969.04
986.06
1970.05
985.53
657.35

SP350
Ac-LTF$r8EYWSQCba$AAAAAa-NH2
359

1957.04
980.04
1958.05
979.53
653.35

SP351
Ac-LTF$r8EYWSQCba$AAAAAa-NH2
360
iso2
1957.04
980.04
1958.05
979.53
653.35

SP352
Ac-LTF$r8EYWAQCba$SAAa-NH2
361

1814.96
909
1815.97
908.49
605.99

SP353
Ac-LTF$r8EYWAQCba$SAAa-NH2
362
iso2
1814.96
909
1815.97
908.49
605.99

SP354
Ac-ALTF$r8EYWAQCba$SAAa-NH2
363

1886
944.52
1887.01
944.01
629.67

SP355
Ac-ALTF$r8EYWAQCba$SAAa-NH2
364
iso2
1886
944.98
1887.01
944.01
629.67

SP356
Ac-ALTF$r8EYWAQCba$SAAAa-NH2
365

1957.04
980.04
1958.05
979.53
653.35

SP357
Ac-ALTF$r8EYWAQCba$SAAAa-NH2
366
iso2
1957.04
980.04
1958.05
979.53
653.35

SP358
Ac-AALTF$r8EYWAQCba$SAAAa-NH2
367

2028.07
1016.1
2029.08
1015.04
677.03

SP359
Ac-AALTF$r8EYWAQCba$SAAAa-NH2
368
iso2
2028.07
1015.57
2029.08
1015.04
677.03

SP360
Ac-RTF$r8EYWAQCba$SAA-NH2
369

1786.94
895.03
1787.95
894.48
596.65

SP361
Ac-LRF$r8EYWAQCba$SAA-NH2
370

1798.98
901.51
1799.99
900.5
600.67

SP362
Ac-LTF$r8EYWRQCba$SAA-NH2
371

1828.99
916.4
1830
915.5
610.67

SP363
Ac-LTF$r8EYWARCba$SAA-NH2
372

1771.97
887.63
1772.98
886.99
591.66

SP364
Ac-LTF$r8EYWAQCba$RAA-NH2
373

1812.99
908.08
1814
907.5
605.34

SP365
Ac-LTF$r8EYWAQCba$SRA-NH2
374

1828.99
916.12
1830
915.5
610.67

SP366
Ac-LTF$r8EYWAQCba$SAR-NH2
375

1828.99
916.12
1830
915.5
610.67

SP367
5-FAM-BaLTF$r8EYWAQCba$SAA-NH2
376

2131
1067.09
2132.01
1066.51
711.34

SP368
5-FAM-BaLTF$r8AYWAQL$AANleA-NH2
377

2158.08
1080.6
2159.09
1080.05
720.37

SP369
Ac-LAF$r8EYWAQL$AANleA-NH2
378

1799
901.05
1800.01
900.51
600.67

SP370
Ac-ATF$r8EYWAQL$AANleA-NH2
379

1786.97
895.03
1787.98
894.49
596.66

SP371
Ac-AAF$r8EYWAQL$AANleA-NH2
380

1756.96
880.05
1757.97
879.49
586.66

SP372
Ac-AAAF$r8EYWAQL$AANleA-NH2
381

1827.99
915.57
1829
915
610.34

SP373
Ac-AAAAF$r8EYWAQL$AANleA-NH2
382

1899.03
951.09
1900.04
950.52
634.02

SP374
Ac-AATF$r8EYWAQL$AANleA-NH2
383

1858
930.92
1859.01
930.01
620.34

SP375
Ac-AALTF$r8EYWAQL$AANleA-NH2
384

1971.09
987.17
1972.1
986.55
658.04

SP376
Ac-AAALTF$r8EYWAQL$AANleA-NH2
385

2042.12
1023.15
2043.13
1022.07
681.71

SP377
Ac-LTF$r8EYWAQL$AANleAA-NH2
386

1900.05
952.02
1901.06
951.03
634.36

SP378
Ac-ALTF$r8EYWAQL$AANleAA-NH2
387

1971.09
987.63
1972.1
986.55
658.04

SP379
Ac-AALTF$r8EYWAQL$AANleAA-NH2
388

2042.12
1022.69
2043.13
1022.07
681.71

SP380
Ac-LTF$r8EYWAQCba$AANleAA-NH2
389

1912.05
958.03
1913.06
957.03
638.36

SP381
Ac-LTF$r8EYWAQhL$AANleAA-NH2
390

1914.07
958.68
1915.08
958.04
639.03

SP382
Ac-ALTF$r8EYWAQhL$AANleAA-NH2
391

1985.1
994.1
1986.11
993.56
662.71

SP383
Ac-LTF$r8ANmYWAQL$AANleA-NH2
392

1785.02
894.11
1786.03
893.52
596.01

SP384
Ac-LTF$r8ANmYWAQL$AANleA-NH2
393
iso2
1785.02
894.11
1786.03
893.52
596.01

SP385
Ac-LTF$r8AYNmWAQL$AANleA-NH2
394

1785.02
894.11
1786.03
893.52
596.01

SP386
Ac-LTF$r8AYNmWAQL$AANleA-NH2
395
iso2
1785.02
894.11
1786.03
893.52
596.01

SP387
Ac-LTF$r8AYAmwAQL$AANleA-NH2
396

1785.02
894.01
1786.03
893.52
596.01

SP388
Ac-LTF$r8AYAmwAQL$AANleA-NH2
397
iso2
1785.02
894.01
1786.03
893.52
596.01

SP389
Ac-LTF$r8AYWAibQL$AANleA-NH2
398

1785.02
894.01
1786.03
893.52
596.01

SP390
Ac-LTF$r8AYWAibQL$AANleA-NH2
399
iso2
1785.02
894.01
1786.03
893.52
596.01

SP391
Ac-LTF$r8AYWAQL$AAibNleA-NH2
400

1785.02
894.38
1786.03
893.52
596.01

SP392
Ac-LTF$r8AYWAQL$AAibNleA-NH2
401
iso2
1785.02
894.38
1786.03
893.52
596.01

SP393
Ac-LTF$r8AYWAQL$AaNleA-NH2
402

1771.01
887.54
1772.02
886.51
591.34

SP394
Ac-LTF$r8AYWAQL$AaNleA-NH2
403
iso2
1771.01
887.54
1772.02
886.51
591.34

SP395
Ac-LTF$r8AYWAQL$ASarNleA-NH2
404

1771.01
887.35
1772.02
886.51
591.34

SP396
Ac-LTF$r8AYWAQL$ASarNleA-NH2
405
iso2
1771.01
887.35
1772.02
886.51
591.34

SP397
Ac-LTF$r8AYWAQL$AANleAib-NH2
406

1785.02
894.75
1786.03
893.52
596.01

SP398
Ac-LTF$r8AYWAQL$AANleAib-NH2
407
iso2
1785.02
894.75
1786.03
893.52
596.01

SP399
Ac-LTF$r8AYWAQL$AANleNmA-NH2
408

1785.02
894.6
1786.03
893.52
596.01

SP400
Ac-LTF$r8AYWAQL$AANleNmA-NH2
409
iso2
1785.02
894.6
1786.03
893.52
596.01

SP401
Ac-LTF$r8AYWAQL$AANleSar-NH2
410

1771.01
886.98
1772.02
886.51
591.34

SP402
Ac-LTF$r8AYWAQL$AANleSar-NH2
411
iso2
1771.01
886.98
1772.02
886.51
591.34

SP403
Ac-LTF$r8AYWAQL$AANleAAib-NH2
412

1856.06

1857.07
929.04
619.69

SP404
Ac-LTF$r8AYWAQL$AANleAAib-NH2
413
iso2
1856.06

1857.07
929.04
619.69

SP405
Ac-LTF$r8AYWAQL$AANleANmA-NH2
414

1856.06
930.37
1857.07
929.04
619.69

SP406
Ac-LTF$r8AYWAQL$AANleANmA-NH2
415
iso2
1856.06
930.37
1857.07
929.04
619.69

SP407
Ac-LTF$r8AYWAQL$AANleAa-NH2
416

1842.04
922.69
1843.05
922.03
615.02

SP408
Ac-LTF$r8AYWAQL$AANleAa-NH2
417
iso2
1842.04
922.69
1843.05
922.03
615.02

SP409
Ac-LTF$r8AYWAQL$AANleASar-NH2
418

1842.04
922.6
1843.05
922.03
615.02

SP410
Ac-LTF$r8AYWAQL$AANleASar-NH2
419
iso2
1842.04
922.6
1843.05
922.03
615.02

SP411
Ac-LTF$/r8AYWAQLVAANleA-NH2
420

1799.04
901.14
1800.05
900.53
600.69

SP412
Ac-LTFAibAYWAQLAibAANleA-NH2
421

1648.9
826.02
1649.91
825.46
550.64

SP413
Ac-LTF$r8Cou4YWAQL$AANleA-NH2
422

1975.05
989.11
1976.06
988.53
659.36

SP414
Ac-LTF$r8Cou4YWAQL$AANleA-NH2
423
iso2
1975.05
989.11
1976.06
988.53
659.36

SP415
Ac-LTF$r8AYWCou4QL$AANleA-NH2
424

1975.05
989.11
1976.06
988.53
659.36

SP416
Ac-LTF$r8AYWAQL$Cou4ANleA-NH2
425

1975.05
989.57
1976.06
988.53
659.36

SP417
Ac-LTF$r8AYWAQL$Cou4ANleA-NH2
426
iso2
1975.05
989.57
1976.06
988.53
659.36

SP418
Ac-LTF$r8AYWAQL$ACou4NleA-NH2
427

1975.05
989.57
1976.06
988.53
659.36

SP419
Ac-LTF$r8AYWAQL$ACou4NleA-NH2
428
iso2
1975.05
989.57
1976.06
988.53
659.36

SP420
Ac-LTF$r8AYWAQL$AANleA-OH
429

1771.99
887.63
1773
887
591.67

SP421
Ac-LTF$r8AYWAQL$AANleA-OH
430
iso2
1771.99
887.63
1773
887
591.67

SP422
Ac-LTF$r8AYWAQL$AANleA-NHnPr
431

1813.05
908.08
1814.06
907.53
605.36

SP423
Ac-LTF$r8AYWAQL$AANleA-NHnPr
432
iso2
1813.05
908.08
1814.06
907.53
605.36

SP424
Ac-LTF$r8AYWAQL$AANleA-NHnBu33Me
433

1855.1
929.17
1856.11
928.56
619.37

SP425
Ac-LTF$r8AYWAQL$AANleA-NHnBu33Me
434
iso2
1855.1
929.17
1856.11
928.56
619.37

SP426
Ac-LTF$r8AYWAQL$AANleA-NHHex
435

1855.1
929.17
1856.11
928.56
619.37

SP427
Ac-LTF$r8AYWAQL$AANleA-NHHex
436
iso2
1855.1
929.17
1856.11
928.56
619.37

SP428
Ac-LTA$r8AYWAQL$AANleA-NH2
437

1694.98
849.33
1695.99
848.5
566

SP429
Ac-LThL$r8AYWAQL$AANleA-NH2
438

1751.04
877.09
1752.05
876.53
584.69

SP430
Ac-LTF$r8AYAAQL$AANleA-NH2
439

1655.97
829.54
1656.98
828.99
553

SP431
Ac-LTF$r8AY2Na1AQL$AANleA-NH2
440

1782.01
892.63
1783.02
892.01
595.01

SP432
Ac-LTF$r8EYWCou4QCba$SAA-NH2
441

1947.97
975.8
1948.98
974.99
650.33

SP433
Ac-LTF$r8EYWCou7QCba$SAA-NH2
442

16.03
974.9
17.04
9.02
6.35

SP434
Ac-LTF%r8EYWAQCba%SAA-NH2
443

1745.94
874.8
1746.95
873.98
582.99

SP435
Dmaac-LTF$r8EYWAQCba$SAA-NH2
444

1786.97
894.8
1787.98
894.49
596.66

SP436
Dmaac-LTF$r8AYWAQL$AAAAAa-NH2
445

1914.08
958.2
1915.09
958.05
639.03

SP437
Dmaac-LTF$r8AYWAQL$AAAAAa-NH2
446
iso2
1914.08
958.2
1915.09
958.05
639.03

SP438
Dmaac-LTF$r8EYWAQL$AAAAAa-NH2
447

1972.08
987.3
1973.09
987.05
658.37

SP439
Dmaac-LTF$r8EYWAQL$AAAAAa-NH2
448
iso2
1972.08
987.3
1973.09
987.05
658.37

SP440
Dmaac-LTF$r8EF4coohWAQCba$AAIa-NH2
449

1912.05
957.4
1913.06
957.03
638.36

SP441
Dmaac-LTF$r8EF4coohWAQCba$AAIa-NH2
450
iso2
1912.05
957.4
1913.06
957.03
638.36

SP442
Dmaac-LTF$r8AYWAQL$AANleA-NH2
451

1814.05
908.3
1815.06
908.03
605.69

SP443
Dmaac-LTF$r8AYWAQL$AANleA-NH2
452
iso2
1814.05
908.3
1815.06
908.03
605.69

SP444
Ac-LTF%r8AYWAQL%AANleA-NH2
453

1773.02
888.37
1774.03
887.52
592.01

SP445
Ac-LTF%r8EYWAQL%AAAAAa-NH2
454

1931.06
966.4
1932.07
966.54
644.69

SP446
Cou6BaLTF$r8EYWAQhL$SAA-NH2
455

2018.05
1009.9
2019.06
1010.03
673.69

SP447
Cou8BaLTF$r8EYWAQhL$SAA-NH2
456

1962.96
982.34
1963.97
982.49
655.32

SP448
Ac-LTF4M8EYWAQL$AAAAAa-NH2
457

2054.93
1028.68
2055.94
1028.47
685.98

SP449
Ac-LTF$r8EYWAQL$AAAAAa-NH2
458

1929.04
966.17
1930.05
965.53
644.02

SP550
Ac-LTF$r8EYWAQL$AAAAAa-OH
459

1930.02
966.54
1931.03
966.02
644.35

SP551
Ac-LTF$r8EYWAQL$AAAAAa-OH
460
iso2
1930.02
965.89
1931.03
966.02
644.35

SP552
Ac-LTF$r8EYWAEL$AAAAAa-NH2
461

1930.02
966.82
1931.03
966.02
644.35

SP553
Ac-LTF$r8EYWAEL$AAAAAa-NH2
462
iso2
1930.02
966.91
1931.03
966.02
644.35

SP554
Ac-LTF$r8EYWAEL$AAAAAa-OH
463

1931.01
967.28
1932.02
966.51
644.68

SP555
Ac-LTF$r8EY6clWAQL$AAAAAa-NH2
464

1963
983.28
1964.01
982.51
655.34

SP556
Ac-LTF$r8EF4b0H2WAQL$AAAAAa-NH2
465

1957.05
980.04
1958.06
979.53
653.36

SP557
Ac-AAALTF$r8EYWAQL$AAAAAa-NH2
466

2142.15
1072.83
2143.16
1072.08
715.06

SP558
Ac-LTF34F2$r8EYWAQL$AAAAAa-NH2
467

1965.02
984.3
1966.03
983.52
656.01

SP559
Ac-RTF$r8EYWAQL$AAAAAa-NH2
468

1972.06
987.81
1973.07
987.04
658.36

SP560
Ac-LTA$r8EYWAQL$AAAAAa-NH2
469

1853.01
928.33
1854.02
927.51
618.68

SP561
Ac-LTF$r8EYWAibQL$AAAAAa-NH2
470

1943.06
973.48
1944.07
972.54
648.69

SP562
Ac-LTF$r8EYWAQL$AAibAAAa-NH2
471

1943.06
973.11
1944.07
972.54
648.69

SP563
Ac-LTF$r8EYWAQL$AAAibAAa-NH2
472

1943.06
973.48
1944.07
972.54
648.69

SP564
Ac-LTF$r8EYWAQL$AAAAibAa-NH2
473

1943.06
973.48
1944.07
972.54
648.69

SP565
Ac-LTF$r8EYWAQL$AAAAAiba-NH2
474

1943.06
973.38
1944.07
972.54
648.69

SP566
Ac-LTF$r8EYWAQL$AAAAAiba-NH2
475
iso2
1943.06
973.38
1944.07
972.54
648.69

SP567
Ac-LTF$r8EYWAQL$AAAAAAib-NH2
476

1943.06
973.01
1944.07
972.54
648.69

SP568
Ac-LTF$r8EYWAQL$AaAAAa-NH2
477

1929.04
966.54
1930.05
965.53
644.02

SP569
Ac-LTF$r8EYWAQL$AAaAAa-NH2
478

1929.04
966.35
1930.05
965.53
644.02

SP570
Ac-LTF$r8EYWAQL$AAAaAa-NH2
479

1929.04
966.54
1930.05
965.53
644.02

SP571
Ac-LTF$r8EYWAQL$AAAaAa-NH2
480
iso2
1929.04
966.35
1930.05
965.53
644.02

SP572
Ac-LTF$r8EYWAQL$AAAAaa-NH2
481

1929.04
966.35
1930.05
965.53
644.02

SP573
Ac-LTF$r8EYWAQL$AAAAAA-NH2
482

1929.04
966.35
1930.05
965.53
644.02

SP574
Ac-LTF$r8EYWAQL$ASarAAAa-NH2
483

1929.04
966.54
1930.05
965.53
644.02

SP575
Ac-LTF$r8EYWAQL$AASarAAa-NH2
484

1929.04
966.35
1930.05
965.53
644.02

SP576
Ac-LTF$r8EYWAQL$AAASarAa-NH2
485

1929.04
966.35
1930.05
965.53
644.02

SP577
Ac-LTF$r8EYWAQL$AAAASara-NH2
486

1929.04
966.35
1930.05
965.53
644.02

SP578
Ac-LTF$r8EYWAQL$AAAAASar-NH2
487

1929.04
966.08
1930.05
965.53
644.02

SP579
Ac-7LTF$r8EYWAQL$AAAAAa-NH2
488

1918.07
951.99
1919.08
960.04
640.37

SP581
Ac-TF$r8EYWAQL$AAAAAa-NH2
489

1815.96
929.85
1816.97
908.99
606.33

SP582
Ac-F$r8EYWAQL$AAAAAa-NH2
490

1714.91
930.92
1715.92
858.46
572.64

SP583
Ac-LVF$r8EYWAQL$AAAAAa-NH2
491

1927.06
895.12
1928.07
964.54
643.36

SP584
Ac-AAF$r8EYWAQL$AAAAAa-NH2
492

1856.98
859.51
1857.99
929.5
620

SP585
Ac-LTF$r8EYWAQL$AAAAa-NH2
493

1858
824.08
1859.01
930.01
620.34

SP586
Ac-LTF$r8EYWAQL$AAAa-NH2
494

1786.97
788.56
1787.98
894.49
596.66

SP587
Ac-LTF$r8EYWAQL$AAa-NH2
495

1715.93
1138.57
1716.94
858.97
572.98

SP588
Ac-LTF$r8EYWAQL$Aa-NH2
496

1644.89
1144.98
1645.9
823.45
549.3

SP589
Ac-LTF$r8EYWAQL$a-NH2
497

1573.85
1113.71
1574.86
787.93
525.62

SP590
Ac-LTF$r8EYWAQL$AAA-OH
498

1716.91
859.55
1717.92
859.46
573.31

SP591
Ac-LTF$r8EYWAQL$A-OH
499

1574.84
975.14
1575.85
788.43
525.95

SP592
Ac-LTF$r8EYWAQL$AAA-NH2
500

1715.93
904.75
1716.94
858.97
572.98

SP593
Ac-LTF$r8EYWAQCba$SAA-OH
501

1744.91
802.49
1745.92
873.46
582.64

SP594
Ac-LTF$r8EYWAQCba$S-OH
502

1602.83
913.53
1603.84
802.42
535.28

SP595
Ac-LTF$r8EYWAQCba$S-NH2
503

1601.85
979.58
1602.86
801.93
534.96

SP596
4-FBz1-LTF$r8EYWAQL$AAAAAa-NH2
504

2009.05
970.52
2010.06
1005.53
670.69

SP597
4-FBz1-LTF$r8EYWAQCba$SAA-NH2
505

1823.93
965.8
1824.94
912.97
608.98

SP598
Ac-LTF$r8RYWAQL$AAAAAa-NH2
506

1956.1
988.28
1957.11
979.06
653.04

SP599
Ac-LTF$r8HYWAQL$AAAAAa-NH2
507

1937.06
1003.54
1938.07
969.54
646.69

SP600
Ac-LTF$r8QYWAQL$AAAAAa-NH2
508

1928.06
993.92
1929.07
965.04
643.69

SP601
Ac-LTF$r8CitYWAQL$AAAAAa-NH2
509

1957.08
987
1958.09
979.55
653.37

SP602
Ac-LTF$r8G1aYWAQL$AAAAAa-NH2
510

1973.03
983
1974.04
987.52
658.68

SP603
Ac-LTF$r8F4gYWAQL$AAAAAa-NH2
511

2004.1
937.86
2005.11
1003.06
669.04

SP604
Ac-LTF$r82mRYWAQL$AAAAAa-NH2
512

1984.13
958.58
1985.14
993.07
662.38

SP605
Ac-LTF$r8ipKYWAQL$AAAAAa-NH2
513

1970.14
944.52
1971.15
986.08
657.72

SP606
Ac-LTF$r8F4NH2YWAQL$AAAAAa-NH2
514

1962.08
946
1963.09
982.05
655.03

SP607
Ac-LTF$r8EYWAAL$AAAAAa-NH2
515

1872.02
959.32
1873.03
937.02
625.01

SP608
Ac-LTF$r8EYWALL$AAAAAa-NH2
516

1914.07
980.88
1915.08
958.04
639.03

SP609
Ac-LTF$r8EYWAAibL$AAAAAa-NH2
517

1886.03
970.61
1887.04
944.02
629.68

SP610
Ac-LTF$r8EYWASL$AAAAAa-NH2
518

1888.01
980.51
1889.02
945.01
630.34

SP611
Ac-LTF$r8EYWANL$AAAAAa-NH2
519

1915.02
1006.41
1916.03
958.52
639.35

SP612
Ac-LTF$r8EYWACitL$AAAAAa-NH2
520

1958.07

1959.08
980.04
653.7

SP613
Ac-LTF$r8EYWAHL$AAAAAa-NH2
521

1938.04
966.24
1939.05
970.03
647.02

SP614
Ac-LTF$r8EYWARL$AAAAAa-NH2
522

1957.08

1958.09
979.55
653.37

SP615
Ac-LTF$r8EpYWAQL$AAAAAa-NH2
523

2009.01

2010.02
1005.51
670.68

SP616
Cbm-LTF$r8EYWAQCba$SAA-NH2
524

1590.85

1591.86
796.43
531.29

SP617
Cbm-LTF$r8EYWAQL$AAAAAa-NH2
525

1930.04

1931.05
966.03
644.35

SP618
Ac-LTF$r8EYWAQL$SAAAAa-NH2
526

1945.04
1005.11
1946.05
973.53
649.35

SP619
Ac-LTF$r8EYWAQL$AAAASa-NH2
527

1945.04
986.52
1946.05
973.53
649.35

SP620
Ac-LTF$r8EYWAQL$SAAASa-NH2
528

1961.03
993.27
1962.04
981.52
654.68

SP621
Ac-LTF$r8EYWAQTba$AAAAAa-NH2
529

1943.06
983.1
1944.07
972.54
648.69

SP622
Ac-LTF$r8EYWAQAdm$AAAAAa-NH2
530

2007.09
990.31
2008.1
1004.55
670.04

SP623
Ac-LTF$r8EYWAQCha$AAAAAa-NH2
531

1969.07
987.17
1970.08
985.54
657.36

SP624
Ac-LTF$r8EYWAQhCha$AAAAAa-NH2
532

1983.09
1026.11
1984.1
992.55
662.04

SP625
Ac-LTF$r8EYWAQF$AAAAAa-NH2
533

1963.02
957.01
1964.03
982.52
655.35

SP626
Ac-LTF$r8EYWAQhF$AAAAAa-NH2
534

1977.04
1087.81
1978.05
989.53
660.02

SP627
Ac-LTF$r8EYWAQL$AANleAAa-NH2
535

1971.09
933.45
1972.1
986.55
658.04

SP628
Ac-LTF$r8EYWAQAdm$AANleAAa-NH2
536

2049.13
1017.97
2050.14
1025.57
684.05

SP629
4-FBz-BaLTF$r8EYWAQL$AAAAAa-NH2
537

2080.08

2081.09
1041.05
694.37

SP630
4-FBz-BaLTF$r8EYWAQCba$SAA-NH2
538

1894.97

1895.98
948.49
632.66

SP631
Ac-LTF$r5EYWAQL$s8AAAAAa-NH2
539

1929.04
1072.68
1930.05
965.53
644.02

SP632
Ac-LTF$r5EYWAQCba$s8SAA-NH2
540

1743.92
1107.79
1744.93
872.97
582.31

SP633
Ac-LTF$r8EYWAQL$AAhhLAAa-NH2
541

1999.12

2000.13
1000.57
667.38

SP634
Ac-LTF$r8EYWAQL$AAAAAAAa-NH2
542

2071.11

2072.12
1036.56
691.38

SP635
Ac-LTF$r8EYWAQL$AAAAAAAAa-NH2
543

2142.15
778.1
2143.16
1072.08
715.06

SP636
Ac-LTF$r8EYWAQL$AAAAAAAAAa-NH2
544

2213.19
870.53
2214.2
1107.6
738.74

SP637
Ac-LTA$r8EYAAQCba$SAA-NH2
545

1552.85

1553.86
777.43
518.62

SP638
Ac-LTA$r8EYAAQL$AAAAAa-NH2
546

1737.97
779.45
1738.98
869.99
580.33

SP639
Ac-LTF$r8EPmpWAQL$AAAAAa-NH2
547

2007.03
779.54
2008.04
1004.52
670.02

SP640
Ac-LTF$r8EPmpWAQCba$SAA-NH2
548

1821.91
838.04
1822.92
911.96
608.31

SP641
Ac-ATF$r8HYWAQL$S-NH2
549

1555.82
867.83
1556.83
778.92
519.61

SP642
Ac-LTF$r8HAWAQL$S-NH2
550

1505.84
877.91
1506.85
753.93
502.95

SP643
Ac-LTF$r8HYWAQA$S-NH2
551

1555.82
852.52
1556.83
778.92
519.61

SP644
Ac-LTF$r8EYWAQCba$SA-NH2
552

1672.89
887.18
1673.9
837.45
558.64

SP645
Ac-LTF$r8EYWAQL$SAA-NH2
553

1731.92
873.32
1732.93
866.97
578.31

SP646
Ac-LTF$r8HYWAQCba$SAA-NH2
554

1751.94
873.05
1752.95
876.98
584.99

SP647
Ac-LTF$r8SYWAQCba$SAA-NH2
555

1701.91
844.88
1702.92
851.96
568.31

SP648
Ac-LTF$r8RYWAQCba$SAA-NH2
556

1770.98
865.58
1771.99
886.5
591.33

SP649
Ac-LTF$r8KYWAQCba$SAA-NH2
557

1742.98
936.57
1743.99
872.5
582

SP650
Ac-LTF$r8QYWAQCba$SAA-NH2
558

1742.94
930.93
1743.95
872.48
581.99

SP651
Ac-LTF$r8EYWAACba$SAA-NH2
559

1686.9
1032.45
1687.91
844.46
563.31

SP652
Ac-LTF$r8EYWAQCba$AAA-NH2
560

1727.93
895.46
1728.94
864.97
576.98

SP653
Ac-LTF$r8EYWAQL$AAAAA-OH
561

1858.99
824.54
1860
930.5
620.67

SP654
Ac-LTF$r8EYWAQL$AAAA-OH
562

1787.95
894.48
1788.96
894.98
596.99

SP655
Ac-LTF$r8EYWAQL$AA-OH
563

1645.88
856
1646.89
823.95
549.63

SP656
Ac-LTF$r8AF4b0H2WAQL$AAAAAa-NH2
564

SP657
Ac-LTF$r8AF4b0H2WAAL$AAAAAa-NH2
565

SP658
Ac-LTF$r8EF4b0H2WAQCba$SAA-NH2
566

SP659
Ac-LTF$r8ApYWAQL$AAAAAa-NH2
567

SP660
Ac-LTF$r8ApYWAAL$AAAAAa-NH2
568

SP661
Ac-LTF$r8EpYWAQCba$SAA-NH2
569

SP662
Ac-LTF$rda6AYWAQL$da5AAAAAa-NH2
570

1974.06
934A4

SP663
Ac-LTF$rda6EYWAQCba$da5SAA-NH2
571

1846.95
870.52

869.94

SP664
Ac-LTF$rda6EYWAQL$da5AAAAAa-NH2
572

SP665
Ac-LTF$ra9EYWAQL$a6AAAAAa-NH2
573

936.57

935.51

SP666
Ac-LTF$ra9EYWAQL$a6AAAAAa-NH2
574

SP667
Ac-LTF$ra9EYWAQCba$a6SAA-NH2
575

SP668
Ac-LTA$ra9EYWAQCba$a6SAA-NH2
576

SP669
5-FAM-BaLTF$ra9EYWAQCba$a6SAA-NH2
577

SP670
5-FAM-BaLTF$r8EYWAQL$AAAAAa-NH2
578

2316.11

SP671
5-FAM-BaLTF$/r8EYWAQLVAAAAAa-NH2
579

2344.15

SP672
5-FAM-BaLTA$r8EYWAQL$AAAAAa-NH2
580

2240.08

SP673
5-FAM-BaLTF$r8AYWAQL$AAAAAa-NH2
581

2258.11

SP674
5-FAM-BaATF$r8EYWAQL$AAAAAa-NH2
582

2274.07

SP675
5-FAM-BaLAF$r8EYWAQL$AAAAAa-NH2
583

2286.1

SP676
5-FAM-BaLTF$r8EAWAQL$AAAAAa-NH2
584

2224.09

SP677
5-FAM-BaLTF$r8EYAAQL$AAAAAa-NH2
585

2201.07

SP678
5-FAM-BaLTA$r8EYAAQL$AAAAAa-NH2
586

2125.04

SP679
5-FAM-BaLTF$r8EYWAAL$AAAAAa-NH2
587

2259.09

SP680
5-FAM-BaLTF$r8EYWAQA$AAAAAa-NH2
588

2274.07

SP681
5-FAM-BaLTF$/r8EYWAQCba$/SAA-NH2
589

2159.03

SP682
5-FAM-BaLTA$r8EYWAQCba$SAA-NH2
590

2054.97

SP683
5-FAM-BaLTF$r8EYAAQCba$SAA-NH2
591

2015.96

SP684
5-FAM-BaLTA$r8EYAAQCba$SAA-NH2
592

1939.92

SP685
5-FAM-BaQSQQTF$r8NLWRLL$QN-NH2
593

2495.23

SP686
5-TAMRA-BaLTF$r8EYWAQCba$SAA-NH2
594

2186.1

SP687
5-TAMRA-BaLTA$r8EYWAQCba$SAA-NH2
595

2110.07

SP688
5-TAMRA-BaLTF$r8EYAAQCba$SAA-NH2
596

2071.06

SP689
5-TAMRA-BaLTA$r8EYAAQCba$SAA-NH2
597

1995.03

SP690
5-TAMRA-BaLTF$/r8EYWAQCba$/SAA-
598

2214.13

NH2

SP691
5-TAMRA-BaLTF$r8EYWAQL$AAAAAa-
599

2371.22

NH2

SP692
5-TAMRA-BaLTA$r8EYWAQL$AAAAAa-
600

2295.19

NH2

SP693
5-TAMRA-BaLTF$/r8EYWAQLVAAAAAa-
601

2399.25

NH2

SP694
Ac-LTF$r8EYWCou7QCba$SAA-OH
602

1947.93

SP695
Ac-LTF$r8EYWCou7QCba$S-OH
603

1805.86

SP696
Ac-LTA$r8EYWCou7QCba$SAA-NH2
604

1870.91

SP697
Ac-LTF$r8EYACou7QCba$SAA-NH2
605

1831.9

SP698
Ac-LTA$r8EYACou7QCba$SAA-NH2
606

1755.87

SP699
Ac-LTF$/r8EYWCou7QCbaS/SAA-NH2
607

1974.98

SP700
Ac-LTF$r8EYWCou7QL$AAAAAa-NH2
608

2132.06

SP701
Ac-LTF$/r8EYWCou7QLVAAAAAa-NH2
609

2160.09

SP702
Ac-LTF$r8EYWCou7QL$AAAAA-OH
610

2062.01

SP703
Ac-LTF$r8EYWCou7QL$AAAA-OH
611

1990.97

SP704
Ac-LTF$r8EYWCou7QL$AAA-OH
612

1919.94

SP705
Ac-LTF$r8EYWCou7QL$AA-OH
613

1848.9

SP706
Ac-LTF$r8EYWCou7QL$A-OH
614

1777.86

SP707
Ac-LTF$r8EYWAQL$AAAASa-NH2
615
iso2

974.4

973.53

SP708
Ac-LTF$r8AYWAAL$AAAAAa-NH2
616
iso2
1814.01
908.82
1815.02
908.01
605.68

SP709
Biotin-BaLTF$r8EYWAQL$AAAAAa-NH2
617

2184.14
1093.64
2185.15
1093.08
729.05

SP710
Ac-LTF$r8HAWAQL$S-NH2
618
iso2
1505.84
754.43
1506.85
753.93
502.95

SP711
Ac-LTF$r8EYWAQCba$SA-NH2
619
iso2
1672.89
838.05
1673.9
837.45
558.64

SP712
Ac-LTF$r8HYWAQCba$SAA-NH2
620
iso2
1751.94
877.55
1752.95
876.98
584.99

SP713
Ac-LTF$r8SYWAQCba$SAA-NH2
621
iso2
1701.91
852.48
1702.92
851.96
568.31

SP714
Ac-LTF$r8RYWAQCba$SAA-NH2
622
iso2
1770.98
887.45
1771.99
886.5
591.33

SP715
Ac-LTF$r8KYWAQCba$SAA-NH2
623
iso2
1742.98
872.92
1743.99
872.5
582

SP716
Ac-LTF$r8EYWAQCba$AAA-NH2
624
iso2
1727.93
865.71
1728.94
864.97
576.98

SP717
Ac-LTF$r8EYWAQL$AAAAAaBaC-NH2
625

2103.09
1053.12
2104.1
1052.55
702.04

SP718
Ac-LTF$r8EYWAQL$AAAAAadPeg4C-NH2
626

2279.19
1141.46
2280.2
1140.6
760.74

SP719
Ac-LTA$r8AYWAAL$AAAAAa-NH2
627

1737.98
870.43
1738.99
870
580.33

SP720
Ac-LTF$r8AYAAAL$AAAAAa-NH2-FAM-B
628

1698.97
851
1699.98
850.49
567.33

SP721
5aLTF$r8AYWAAL$AAAAAa-NH2
629

2201.09
1101.87
2202.1
1101.55
734.7

SP722
Ac-LTA$r8AYWAQL$AAAAAa-NH2
630

1795
898.92
1796.01
898.51
599.34

SP723
Ac-LTF$r8AYAAQL$AAAAAa-NH2
631

1755.99
879.49
1757
879
586.34

SP724
Ac-LTF$rda6AYWAAL$da5AAAAAa-NH2
632

1807.97
1808.98
904.99
603.66

SP725
FITC-BaLTF$r8EYWAQL$AAAAAa-NH2
633

2347.1
1174.49
2348.11
1174.56
783.37

SP726
FITC-BaLTF$r8EYWAQCba$SAA-NH2
634

2161.99
1082.35
2163
1082
721.67

SP733
Ac-LTF$r8EYWAQL$EAAAAa-NH2
635

1987.05
995.03
1988.06
994.53
663.36

SP734
Ac-LTF$r8AYWAQL$EAAAAa-NH2
636

1929.04
966.35
1930.05
965.53
644.02

SP735
Ac-LTF$r8EYWAQL$AAAAAaBaKbio-NH2
637

2354.25
1178.47
2355.26
1178.13
785.76

SP736
Ac-LTF$r8AYWAAL$AAAAAa-NH2
638

1814.01
908.45
1815.02
908.01
605.68

SP737
Ac-LTF$r8AYAAAL$AAAAAa-NH2
639
iso2
1698.97
850.91
1699.98
850.49
567.33

SP738
Ac-LTF$r8AYAAQL$AAAAAa-NH2
640
iso2
1755.99
879.4
1757
879
586.34

SP739
Ac-LTF$r8EYWAQL$EAAAAa-NH2
641
iso2
1987.05
995.21
1988.06
994.53
663.36

SP740
Ac-LTF$r8AYWAQL$EAAAAa-NH2
642
iso2
1929.04
966.08
1930.05
965.53
644.02

SP741
Ac-LTF$r8EYWAQCba$SAAAAa-NH2
643

1957.04
980.04
1958.05
979.53
653.35

SP742
Ac-LTF$r8EYWAQLStAAA$r5AA-NH2
644

2023.12
1012.83
2024.13
1012.57
675.38

SP743
Ac-LTF$r8EYWAQL$A$AAA$A-NH2
645

2108.17
1055.44
2109.18
1055.09
703.73

SP744
Ac-LTF$r8EYWAQL$AA$AAA$A-NH2
646

2179.21
1090.77
2180.22
1090.61
727.41

SP745
Ac-LTF$r8EYWAQL$AAA$AAA$A-NH2
647

2250.25
1126.69
2251.26
1126.13
751.09

SP746
Ac-AAALTF$r8EYWAQL$AAA-OH
648

1930.02

1931.03
966.02
644.35

SP747
Ac-AAALTF$r8EYWAQL$AAA-NH2
649

1929.04
965.85
1930.05
965.53
644.02

SP748
Ac-AAAALTF$r8EYWAQL$AAA-NH2
650

2000.08
1001.4
2001.09
1001.05
667.7

SP749
Ac-AAAAALTF$r8EYWAQL$AAA-NH2
651

2071.11
1037.13
2072.12
1036.56
691.38

SP750
Ac-AAAAAALTF$r8EYWAQL$AAA-NH2
652

2142.15

2143.16
1072.08
715.06

SP751
Ac-LTF$rda6EYWAQCba$da6SAA-NH2
653
iso2
1751.89
877.36
1752.9
876.95
584.97

SP752
Ac-t$r5wya$r5f4CF3e1d1r-NH2
654

844.25

SP753
Ac-tawy$r5nf4CF3e$r511r-NH2
655

837.03

SP754
Ac-tawya$r5f4CF3ek$r51r-NH2
656

822.97

SP755
Ac-tawyanf4CF3e$r511r$r5a-NH2
657

908.35

SP756
Ac-t$s8wyanf4CF3e$r511r-NH2
658

858.03

SP757
Ac-tawy$s8nf4CF3ek11$r5a-NH2
659

879.86

SP758
Ac-tawya$s8f4CF3e1d1r$r5a-NH2
660

936.38

SP759
Ac-tawy$s8naek11$r5a-NH2
661

844.25

SP760
5-FAM-Batawy$s8nf4CF3e1d1$r5a-NH2
662

SP761
5-FAM-Batawy$s8naek11$r5a-NH2
663

SP762
Ac-tawy$s8nf4CF3ea11$r5a-NH2
664

SP763
Ac-tawy$s8nf4CF3e1d1$r5aaaaa-NH2
665

SP764
Ac-tawy$s8nf4CF3ea11$r5aaaaa-NH2
666

Table 1a shows a selection of peptidomimetic macrocycles.

TABLE 1a

SEQ

ID
Iso-
Found
Exact
Calc
Cale
Calc

SP
Sequence
NO:
mer
Mass
Mass
(M + 1)/1
(M + 2)/2
(M + 3)/3

SP244
Ac-LTF$r8EF4coohWAQCba$SANleA-NH2
667

1885
943.59
1886.01
943.51
629.34

sp331
Ac-LTF$r8EYWAQL$AAAAAa-NH2
668
iso2
1929.04
966.08
1930.05
965.53
644.02

SP555
Ac-LTF$r8EY6clWAQL$AAAAAa-NH2
669

1963
983.28
1964.01
982.51
655.34

SP557
Ac-AAALTF$r8EYWAQL$AAAAAa-NH2
670

2142.15
1072.83
2143.16
1072.08
715.06

SP558
Ac-LTF34F2$r8EYWAQL$AAAAAa-NH2
671

1965.02
984.3
1966.03
983.52
656.01

SP562
Ac-LTF$r8EYWAQL$AAibAAAa-NH2
672

1943.06
973.11
1944.07
972.54
648.69

SP564
Ac-LTF$r8EYWAQL$AAAAibAa-NH2
673

1943.06
973.48
1944.07
972.54
648.69

SP566
Ac-LTF$r8EYWAQL$AAAAAiba-NH2
674
iso2
1943.06
973.38
1944.07
972.54
648.69

SP567
Ac-LTF$r8EYWAQL$AAAAAAib-NH2
675

1943.06
973.01
1944.07
972.54
648.69

SP572
Ac-LTF$r8EYWAQL$AAAAaa-NH2
676

1929.04
966.35
1930.05
965.53
644.02

SP573
Ac-LTF$r8EYWAQL$AAAAAA-NH2
677

1929.04
966.35
1930.05
965.53
644.02

SP578
Ac-LTF$r8EYWAQL$AAAAASar-NH2
678

1929.04
966.08
1930.05
965.53
644.02

SP551
Ac-LTF$r8EYWAQL$AAAAAa-OH
679
iso2
1930.02
965.89
1931.03
966.02
644.35

SP662
Ac-LTF$rda6AYWAQL$da5AAAAAa-NH2
680

1974.06
934.44

933.49

SP367
5-FAM-BaLTF$r8EYWAQCba$SAA-NH2
681

2131
1067.09
2132.01
1066.51
711.34

SP349
Ac-LTF$r8EF4coohWAQCba$AAAAAa-NH2
682
iso2
1969.04
986.06
1970.05
985.53
657.35

SP347
Ac-LTF$r8EYWAQCba$AAAAAa-NH2
683
iso2
1941.04
972.55
1942.05
971.53
648.02

Table 1b shows a further selection of peptidomimetic macrocycles.

TABLE 1b

SEQ

ID

Exact
Found
Calc
Cale
Calc

SP
Sequence
NO:
Isomer
Mass
Mass
(M + 1)/1
(M + 2)/2
(M + 3)/3

SP581
Ac-TF$r8EYWAQL$AAAAAa-NH2
684

1815.96
929.85
1816.97
908.99
606.33

SP582
Ac-F$r8EYWAQL$AAAAAa-NH2
685

1714.91
930.92
1715.92
858.46
572.64

SP583
Ac-LVF$r8EYWAQL$AAAAAa-NH2
686

1927.06
895.12
1928.07
964.54
643.36

SP584
Ac-AAF$r8EYWAQL$AAAAAa-NH2
687

1856.98
859.51
1857.99
929.5
620

SP585
Ac-LTF$r8EYWAQL$AAAAa-NH2
688

1858
824.08
1859.01
930.01
620.34

SP586
Ac-LTF$r8EYWAQL$AAAa-NH2
689

1786.97
788.56
1787.98
894.49
596.66

SP587
Ac-LTF$r8EYWAQL$AAa-NH2
690

1715.93
1138.57
1716.94
858.97
572.98

SP588
Ac-LTF$r8EYWAQL$Aa-NH2
691

1644.89
1144.98
1645.9
823.45
549.3

SP589
Ac-LTF$r8EYWAQL$a-NH2
692

1573.85
1113.71
1574.86
787.93
525.62

In the sequences shown above and elsewhere, the following abbreviations are used: “Nle” represents norleucine, “Aib” represents 2-aminoisobutyric acid, “Ac” represents acetyl, and “Pr” represents propionyl. Amino acids represented as “$” are alpha-Me S5-pentenyl-alanine olefin amino acids connected by an all-carbon crosslinker comprising one double bond. Amino acids represented as “$r5” are alpha-Me R5-pentenyl-alanine olefin amino acids connected by an all-carbon comprising one double bond. Amino acids represented as “$s8” are alpha-Me S8-octenyl-alanine olefin amino acids connected by an all-carbon crosslinker comprising one double bond. Amino acids represented as “$r8” are alpha-Me R8-octenyl-alanine olefin amino acids connected by an all-carbon crosslinker comprising one double bond. “Ahx” represents an aminocyclohexyl linker. The crosslinkers are linear all-carbon crosslinker comprising eight or eleven carbon atoms between the alpha carbons of each amino acid. Amino acids represented as “$/” are alpha-Me S5-pentenyl-alanine olefin amino acids that are not connected by any crosslinker. Amino acids represented as “$/r5” are alpha-Me R5-pentenyl-alanine olefin amino acids that are not connected by any crosslinker. Amino acids represented as “$/s8” are alpha-Me S8-octenyl-alanine olefin amino acids that are not connected by any crosslinker. Amino acids represented as “$/r8” are alpha-Me R8-octenyl-alanine olefin amino acids that are not connected by any crosslinker. Amino acids represented as “Amw” are alpha-Me tryptophan amino acids. Amino acids represented as “Aml” are alpha-Me leucine amino acids. Amino acids represented as “Amf” are alpha-Me phenylalanine amino acids. Amino acids represented as “2ff” are 2-fluoro-phenylalanine amino acids. Amino acids represented as “3ff” are 3-fluoro-phenylalanine amino acids. Amino acids represented as “St” are amino acids comprising two pentenyl-alanine olefin side chains, each of which is crosslinked to another amino acid as indicated. Amino acids represented as “St//” are amino acids comprising two pentenyl-alanine olefin side chains that are not crosslinked. Amino acids represented as “% St” are amino acids comprising two pentenyl-alanine olefin side chains, each of which is crosslinked to another amino acid as indicated via fully saturated hydrocarbon crosslinks. Amino acids represented as “Ba” are beta-alanine. The lower-case character “e” or “z” within the designation of a crosslinked amino acid (e.g. “$er8” or “$zr8”) represents the configuration of the double bond (E or Z, respectively). In other contexts, lower-case letters such as “a” or “f” represent D amino acids (e.g. D-alanine, or D-phenylalanine, respectively). Amino acids designated as “NmW” represent N-methyltryptophan. Amino acids designated as “NmY” represent N-methyltyrosine. Amino acids designated as “NmA” represent N-methylalanine. “Kbio” represents a biotin group attached to the side chain amino group of a lysine residue. Amino acids designated as “Sar” represent sarcosine. Amino acids designated as “Cha” represent cyclohexyl alanine. Amino acids designated as “Cpg” represent cyclopentyl glycine. Amino acids designated as “Chg” represent cyclohexyl glycine. Amino acids designated as “Cba” represent cyclobutyl alanine. Amino acids designated as “F4I” represent 4-iodo phenylalanine. “7L” represents N15 isotopic leucine. Amino acids designated as “F3Cl” represent 3-chloro phenylalanine. Amino acids designated as “F4cooh” represent 4-carboxy phenylalanine. Amino acids designated as “F34F2” represent 3,4-difluoro phenylalanine. Amino acids designated as “6clW” represent 6-chloro tryptophan. Amino acids designated as “$rda6” represent alpha-Me R6-hexynyl-alanine alkynyl amino acids, crosslinked via a dialkyne bond to a second alkynyl amino acid. Amino acids designated as “$da5” represent alpha-Me S5-pentynyl-alanine alkynyl amino acids, wherein the alkyne forms one half of a dialkyne bond with a second alkynyl amino acid. Amino acids designated as “$ra9” represent alpha-Me R9-nonynyl-alanine alkynyl amino acids, crosslinked via an alkyne metathesis reaction with a second alkynyl amino acid. Amino acids designated as “$a6” represent alpha-Me S6-hexynyl-alanine alkynyl amino acids, crosslinked via an alkyne metathesis reaction with a second alkynyl amino acid. The designation “iso1” or “iso2” indicates that the peptidomimetic macrocycle is a single isomer.

Amino acids designated as “Cit” represent citrulline. Amino acids designated as “Cou4”, “Cou6”, “Cou7” and “Cou8”, respectively, represent the following structures:

embedded image

In some embodiments, a peptidomimetic macrocycle is obtained in more than one isomer, for example due to the configuration of a double bond within the structure of the crosslinker (E vs Z). Such isomers can or can not be separable by conventional chromatographic methods. In some embodiments, one isomer has improved biological properties relative to the other isomer. In one embodiment, an E crosslinker olefin isomer of a peptidomimetic macrocycle has better solubility, better target affinity, better in vivo or in vitro efficacy, higher helicity, or improved cell permeability relative to its Z counterpart. In another embodiment, a Z crosslinker olefin isomer of a peptidomimetic macrocycle has better solubility, better target affinity, better in vivo or in vitro efficacy, higher helicity, or improved cell permeability relative to its E counterpart.

Table 1c shows exemplary peptidomimetic macrocycle:

TABLE 1c

Structure

SP154 (SEQ ID NO: 163)

embedded image

SP115 (SEQ ID NO: 124)

embedded image

SP114 (SEQ ID NO: 123)

embedded image

SP99 (SEQ ID NO: 108)

embedded image

SP388 (SEQ ID NO: 397)

embedded image

SP331 (SEQ ID NO: 340)

embedded image

SP445 (SEQ ID NO: 454)

embedded image

SP351 (SEQ ID NO: 360)

embedded image

SP71 (SEQ ID NO: 80)

embedded image

SP69 (SEQ ID NO: 78)

embedded image

SP7 (SEQ ID NO: 16)

embedded image

SP160 (SEQ ID NO: 169)

embedded image

SP315 (SEQ ID NO: 324)

embedded image

SP249 (SEQ ID NO: 258)

embedded image

SP437 (SEQ ID NO: 446)

embedded image

SP349 (SEQ ID NO: 358)

embedded image

SP555 (SEQ ID NO: 464)

embedded image

SP557 (SEQ ID NO: 466)

embedded image

SP558 (SEQ ID NO: 467)

embedded image

SP367 (SEQ ID NO: 376)

embedded image

SP562 (SEQ ID NO: 471)

embedded image

SP564 (SEQ ID NO: 473)

embedded image

SP566 (SEQ ID NO: 475)

embedded image

SP567 (SEQ ID NO: 476)

embedded image

SP572 (SEQ ID NO: 480)

embedded image

SP573 (SEQ ID NO: 482)

embedded image

SP578 (SEQ ID NO: 487)

embedded image

SP664 (SEQ ID NO: 572)

embedded image

SP662 (SEQ ID NO: 570)

embedded image

(SEQ ID NO: 1500)

embedded image

In some embodiments, peptidomimetic macrocycles exclude peptidomimetic macrocycles shown in Table 2a:

TABLE 2a

Number
Sequence
SEQ ID NO:

1
L$r5QETFSD$s8WKLLPEN
693

2
LSQ$r5TFSDLW$s8LLPEN
694

3
LSQE$r5FSDLWK$s8LPEN
695

4
LSQET$r5SDLWKL$s8PEN
696

5
LSQETF$r5DLWKLL$s8EN
697

6
LXQETFS$r5LWKLLP$s8N
698

7
LSQETFSD$r5WKLLPE$s8
699

8
LSQQTF$r5DLWKLL$s8EN
700

9
LSQETF$r5DLWKLL$s8QN
701

10
LSQQTF$r5DLWKLL$s8QN
702

11
LSQETF$r5NLWKLL$s8QN
703

12
LSQQTF$r5NLWKLL$s8QN
704

13
LSQQTF$r5NLWRLL$s8QN
705

14
QSQQTF$r5NLWKLL$s8QN
706

15
QSQQTF$r5NLWRLL$s8QN
707

16
QSQQTA$r5NLWRLL$s8QN
708

17
L$r8QETFSD$WKLLPEN
709

18
LSQ$r8TFSDLW$LLPEN
710

19
LSQE$r8FSDLWK$LPEN
711

20
LSQET$r8SDLWKL$PEN
712

21
LSQETF$r8DLWKLL$EN
713

22
LXQETFS$r8LWKLLP$N
714

23
LSQETFSD$r8WKLLPE$
715

24
LSQQTF$r8DLWKLL$EN
716

25
LSQETF$r8DLWKLL$QN
717

26
LSQQTF$r8DLWKLL$QN
718

27
LSQETF$r8NLWKLL$QN
719

28
LSQQTF$r8NLWKLL$QN
720

29
LSQQTF$r8NLWRLL$QN
721

30
QSQQTF$r8NLWKLL$QN
722

31
QSQQTF$r8NLWRLL$QN
723

32
QSQQTA$r8NLWRLL$QN
724

33
QSQQTF$r8NLWRKK$QN
725

34
QQTF$r8DLWRLL$EN
726

35
QQTF$r8DLWRLL$
727

36
LSQQTF$DLW$LL
728

37
QQTF$DLW$LL
729

38
QQTA$r8DLWRLL$EN
730

39
QSQQTF$r5NLWRLL$s8QN
731

(dihydroxylated olefin)

40
QSQQTA$r5NLWRLL$s8QN
732

(dihydroxylated olefin)

41
QSQQTF$r8DLWRLL$QN
733

42
QTF$r8NLWRLL$
734

43
QSQQTF$NLW$LLPQN
735

44
QS$QTF$NLWRLLPQN
736

45
$TFS$LWKLL
737

46
ETF$DLW$LL
738

47
QTF$NLW$LL
739

48
$SQE$FSNLWKLL
740

In Table 2a, X represents S or any amino acid. Peptides shown can comprise an N-terminal capping group such as acetyl or an additional linker such as beta-alanine between the capping group and the start of the peptide sequence.

In some embodiments, peptidomimetic macrocycles do not comprise a peptidomimetic macrocycle structure as shown in Table 2a.

In other embodiments, peptidomimetic macrocycles exclude peptidomimetic macrocycles shown in Table 2b:

TABLE 2b

SEQ

Observed

ID
Exact

mass

Number
Sequence
NO:
Mass
M + 2
(m/e)

1
Ac-LSQETF$r8DLWKLL$EN-NH2
741
2068.13
1035.07
1035.36

2
Ac-LSQETF$r8NLWKLL$QN-NH2
742
2066.16
1034.08
1034.31

3
Ac-LSQQTF$r8NLWRLL$QN-NH2
743
2093.18
1047.59
1047.73

4
Ac-QSQQTF$r8NLWKLL$QN-NH2
744
2080.15
1041.08
1041.31

5
Ac-QSQQTF$r8NLWRLL$QN-NH2
745
2108.15
1055.08
1055.32

6
Ac-QSQQTA$r8NLWRLL$QN-NH2
746
2032.12
1017.06
1017.24

7
Ac-QAibQQTF$r8NLWRLL$QN-NH2
747
2106.17
1054.09
1054.34

8
Ac-QSQQTFSNLWRLLPQN-NH2
748
2000.02
1001.01
1001.26

9
Ac-QSQQTF$/r8NLWRLL$/QN-NH2
749
2136.18
1069.09
1069.37

10
Ac-QSQAibTF$r8NLWRLL$QN-NH2
750
2065.15
1033.58
1033.71

11
Ac-QSQQTF$r8NLWRLL$AN-NH2
751
2051.13
1026.57
1026.70

12
Ac-ASQQTF$r8NLWRLL$QN-NH2
752
2051.13
1026.57
1026.90

13
Ac-QSQQTF$r8ALWRLL$QN-NH2
753
2065.15
1033.58
1033.41

14
Ac-QSQETF$r8NLWRLL$QN-NH2
754
2109.14
1055.57
1055.70

15
Ac-RSQQTF$r8NLWRLL$QN-NH2
755
2136.20
1069.10
1069.17

16
Ac-RSQQTF$r8NLWRLL$EN-NH2
756
2137.18
1069.59
1069.75

17
Ac-LSQETFSDLWKLLPEN-NH2
757
1959.99
981.00
981.24

18
Ac-QSQ$TFS$LWRLLPQN-NH2
758
2008.09
1005.05
1004.97

19
Ac-QSQQ$FSN$WRLLPQN-NH2
759
2036.06
1019.03
1018.86

20
Ac-QSQQT$SNL$RLLPQN-NH2
760
1917.04
959.52
959.32

21
Ac-QSQQTF$NLW$LLPQN-NH2
761
2007.06
1004.53
1004.97

22
Ac-RTQATF$r8NQWAibAN1e$TNAibTR-
762
2310.26
1156.13
1156.52

NH2

23
Ac-QSQQTF$r8NLWRLL$RN-NH2
763
2136.20
1069.10
1068.94

24
Ac-QSQRTF$r8NLWRLL$QN-NH2
764
2136.20
1069.10
1068.94

25
Ac-QSQQTF$r8NNleWRLL$QN-NH2
765
2108.15
1055.08
1055.44

26
Ac-QSQQTF$r8NLWRNleL$QN-NH2
766
2108.15
1055.08
1055.84

27
Ac-QSQQTF$r8NLWRLNle$QN-NH2
767
2108.15
1055.08
1055.12

28
Ac-QSQQTY$r8NLWRLL$QN-NH2
768
2124.15
1063.08
1062.92

29
Ac-RAibQQTF$r8NLWRLL$QN-NH2
769
2134.22
1068.11
1068.65

30
Ac-MPRFMDYWEGLN-NH2
770
1598.70
800.35
800.45

31
Ac-RSQQRF$r8NLWRLL$QN-NH2
771
2191.25
1096.63
1096.83

32
Ac-QSQQRF$r8NLWRLL$QN-NH2
772
2163.21
1082.61
1082.87

33
Ac-RAibQQRF$r8NLWRLL$QN-NH2
773
2189.27
1095.64
1096.37

34
Ac-RSQQRF$r8NFWRLL$QN-NH2
774
2225.23
1113.62
1114.37

35
Ac-RSQQRF$r8NYWRLL$QN-NH2
775
2241.23
1121.62
1122.37

36
Ac-RSQQTF$r8NLWQLL$QN-NH2
776
2108.15
1055.08
1055.29

37
Ac-QSQQTF$r8NLWQAm1L$QN-NH2
777
2094.13
1048.07
1048.32

38
Ac-QSQQTF$r8NAm1WRLL$QN-NH2
778
2122.17
1062.09
1062.35

39
Ac-NlePRF$r8DYWEGL$QN-NH2
779
1869.98
935.99
936.20

40
Ac-NlePRF$r8NYWRLL$QN-NH2
780
1952.12
977.06
977.35

41
Ac-RF$r8NLWRLL$Q-NH2
781
1577.96
789.98
790.18

42
Ac-QSQQTF$r8N2ffWRLL$QN-NH2
782
2160.13
1081.07
1081.40

43
Ac-QSQQTF$r8N3ffWRLL$QN-NH2
783
2160.13
1081.07
1081.34

44
Ac-QSQQTF#r8NLWRLL#QN-NH2
784
2080.12
1041.06
1041.34

45
Ac-RSQQTA$r8NLWRLL$QN-NH2
785
2060.16
1031.08
1031.38

46
Ac-QSQQTF%r8NLWRLL%QN-NH2
786
2110.17
1056.09
1056.55

47
HepQSQ$TFSNLWRLLPQN-NH2
787
2051.10
1026.55
1026.82

48
HepQSQ$TF$r8NLWRLL$QN-NH2
788
2159.23
1080.62
1080.89

49
Ac-QSQQTF$r8NL6clWRLL$QN-NH2
789
2142.11
1072.06
1072.35

50
Ac-QSQQTF$r8NLMe6clwRLL$QN-NH2
790
2156.13
1079.07
1079.27

51
Ac-LTFEHYWAQLTS-NH2
791
1535.74
768.87
768.91

52
Ac-LTF$HYW$QLTS-NH2
792
1585.83
793.92
794.17

53
Ac-LTFE$YWA$LTS-NH2
793
1520.79
761.40
761.67

54
Ac-LTF$zr8HYWAQL$zS-NH2
794
1597.87
799.94
800.06

55
Ac-LTF$r8HYWRQL$S-NH2
795
1682.93
842.47
842.72

56
Ac-QS$QTFStNLWRLL$s8QN-NH2
796
2145.21
1073.61
1073.90

57
Ac-QSQQTASNLWRLLPQN-NH2
797
1923.99
963.00
963.26

58
Ac-QSQQTA$/r8NLWRLL$/QN-NH2
798
2060.15
1031.08
1031.24

59
Ac-ASQQTF$/r8NLWRLL$/QN-NH2
799
2079.16
1040.58
1040.89

60
Ac-$SQQ$FSNLWRLLAibQN-NH2
800
2009.09
1005.55
1005.86

61
Ac-QS$QTF$NLWRLLAibQN-NH2
801
2023.10
1012.55
1012.79

62
Ac-QSQQ$FSN$WRLLAibQN-NH2
802
2024.06
1013.03
1013.31

63
Ac-QSQQTF$NLW$LLAibQN-NH2
803
1995.06
998.53
998.87

64
Ac-QSQQTFS$LWR$LAibQN-NH2
804
2011.06
1006.53
1006.83

65
Ac-QSQQTFSNLW$LLA$N-NH2
805
1940.02
971.01
971.29

66
Ac-$/SQQ$/FSNLWRLLAibQN-NH2
806
2037.12
1019.56
1019.78

67
Ac-QS$/QTF$/NLWRLLAibQN-NH2
807
2051.13
1026.57
1026.90

68
Ac-QSQQ$/FSN$RLLAibQN-NH2
808
2052.09
1027.05
1027.36

69
Ac-QSQQTF$/NLW$/LLAibQN-NH2
809
2023.09
1012.55
1013.82

70
Ac-QSQ$TFS$LWRLLAibQN-NH2
810
1996.09
999.05
999.39

71
Ac-QSQ$/TFS$/LWRLLAibQN-NH2
811
2024.12
1013.06
1013.37

72
Ac-QS$/QTFSWNLWRLL$/s8QN-NH2
812
2201.27
1101.64
1102.00

73
Ac-$r8SQQTFS$LWRLLAibQN-NH2
813
2038.14
1020.07
1020.23

74
Ac-QSQ$r8TFSNLW$LLAibQN-NH2
814
1996.08
999.04
999.32

75
Ac-QSQQTFS$r8LWRLLA$N-NH2
815
2024.12
1013.06
1013.37

76
Ac-QS$r5QTFStNLW$LLAibQN-NH2
816
2032.12
1017.06
1017.39

77
Ac-$/r8SQQTFS$/LWRLLAibQN-NH2
817
2066.17
1034.09
1034.80

78
Ac-QSQ$/r8TFSNLW$/LLAibQN-NH2
818
2024.11
1013.06
1014.34

79
Ac-QSQQTFS$/r8LWRLLA$/N-NH2
819
2052.15
1027.08
1027.16

80
Ac-QS$/r5QTFSt//NLW$/LLAibQN-NH2
820
2088.18
1045.09
1047.10

81
Ac-QSQQTFSNLWRLLAibQN-NH2
821
1988.02
995.01
995.31

82
Hep/QSQ$/TF$/r8NLWRLL$/QN-NH2
822
2215.29
1108.65
1108.93

83
Ac-ASQQTF$r8NLRWLL$QN-NH2
823
2051.13
1026.57
1026.90

84
Ac-QSQQTF$/r8NLWRLL$/Q-NH2
824
2022.14
1012.07
1012.66

85
Ac-QSQQTF$r8NLWRLL$Q-NH2
825
1994.11
998.06
998.42

86
Ac-AAARAA$r8AAARAA$AA-NH2
826
1515.90
758.95
759.21

87
Ac-LTFEHYWAQLTSA-NH2
827
1606.78
804.39
804.59

88
Ac-LTF$r8HYWAQL$SA-NH2
828
1668.90
835.45
835.67

89
Ac-ASQQTFSNLWRLLPQN-NH2
829
1943.00
972.50
973.27

90
Ac-QS$QTFStNLW$r5LLAibQN-NH2
830
2032.12
1017.06
1017.30

91
Ac-QSQQTFAibNLWRLLAibQN-NH2
831
1986.04
994.02
994.19

92
Ac-QSQQTFNleNLWRLLNleQN-NH2
832
2042.11
1022.06
1022.23

93
Ac-QSQQTF$/r8NLWRLLAibQN-NH2
833
2082.14
1042.07
1042.23

94
Ac-QSQQTF$/r8NLWRLLNleQN-NH2
834
2110.17
1056.09
1056.29

95
Ac-QSQQTFAibNLWRLL$/QN-NH2
835
2040.09
1021.05
1021.25

96
Ac-QSQQTFNleNLWRLL$/QN-NH2
836
2068.12
1035.06
1035.31

97
Ac-QSQQTF%r8NL6clWRNleL%QN-NH2
837
2144.13
1073.07
1073.32

98
Ac-QSQQTF%r8NLMe6clWRLL%QN-NH2
838
2158.15
1080.08
1080.31

101
Ac-FNle$YWE$L-NH2
839
1160.63
-
1161.70

102
Ac-F$r8AYWELL$A-NH2
840
1344.75
-
1345.90

103
Ac-F$r8AYWQLL$A-NH2
841
1343.76
-
1344.83

104
Ac-NlePRF$r8NYWELL$QN-NH2
842
1925.06
963.53
963.69

105
Ac-NlePRF$r8DYWRLL$QN-NH2
843
1953.10
977.55
977.68

106
Ac-NlePRF$r8NYWRLL$Q-NH2
844
1838.07
920.04
920.18

107
Ac-NlePRF$r8NYWRLL$-NH2
845
1710.01
856.01
856.13

108
Ac-QSQQTF$r8DLWRLL$QN-NH2
846
2109.14
1055.57
1055.64

109
Ac-QSQQTF$r8NLWRLL$EN-NH2
847
2109.14
1055.57
1055.70

110
Ac-QSQQTF$r8NLWRLL$QD-NH2
848
2109.14
1055.57
1055.64

111
Ac-QSQQTF$r8NLWRLL$S-NH2
849
1953.08
977.54
977.60

112
Ac-ESQQTF$r8NLWRLL$QN-NH2
850
2109.14
1055.57
1055.70

113
Ac-LTF$r8NLWRNleL$Q-NH2
851
1635.99
819.00
819.10

114
Ac-LRF$r8NLWRNleL$Q-NH2
852
1691.04
846.52
846.68

115
Ac-QSQQTF$r8NWWRNleL$QN-NH2
853
2181.15
1091.58
1091.64

116
Ac-QSQQTF$r8NLWRNleL$Q-NH2
854
1994.11
998.06
998.07

117
Ac-QTF$r8NLWRNleL$QN-NH2
855
1765.00
883.50
883.59

118
Ac-NlePRF$r8NWWRLL$QN-NH2
856
1975.13
988.57
988.75

119
Ac-NlePRF$r8NWWRLL$A-NH2
857
1804.07
903.04
903.08

120
Ac-TSFAEYWNLLNH2
858
1467.70
734.85
734.90

121
Ac-QTF$r8HWWSQL$S-NH2
859
1651.85
826.93
827.12

122
Ac-FM$YWE$L-NH2
860
1178.58
-
1179.64

123
Ac-QTFEHWWSQLLS-NH2
861
1601.76
801.88
801.94

124
Ac-QSQQTF$r8NLAmwRLNle$QN-NH2
862
2122.17
1062.09
1062.24

125
Ac-FMAibY6clWEAc3cL-NH2
863
1130.47
-
1131.53

126
Ac-FNle$Y6clWE$L-NH2
864
1194.59
-
1195.64

127
Ac-F$zr8AY6clWEAc3cL$z-NH2
865
1277.63
639.82
1278.71

128
Ac-F$r8AY6clWEAc3cL$A-NH2
866
1348.66
-
1350.72

129
Ac-NlePRF$r8NY6clWRLL$QN-NH2
867
1986.08
994.04
994.64

130
Ac-AF$r8AAWALA$A-NH2
868
1223.71
-
1224.71

131
Ac-TF$r8AAWRLA$Q-NH2
869
1395.80
698.90
399.04

132
Pr-TF$r8AAWRLA$Q-NH2
870
1409.82
705.91
706.04

133
Ac-QSQQTF%r8NLWRNleL%QN-NH2
871
2110.17
1056.09
1056.22

134
Ac-LTF%r8HYWAQL%SA-NH2
872
1670.92
836.46
836.58

135
Ac-NlePRF%r8NYWRLL%QN-NH2
873
1954.13
978.07
978.19

136
Ac-NlePRF%r8NY6clWRLL%QN-NH2
874
1988.09
995.05
995.68

137
Ac-LTF%r8HY6clWAQL%S-NH2
875
1633.84
817.92
817.93

138
Ac-QS%QTF%StNLWRLL%s8QN-NH2
876
2149.24
1075.62
1075.65

139
Ac-LTF%r8HY6clWRQL%S-NH2
877
1718.91
860.46
860.54

140
Ac-QSQQTF%r8NL6clWRLL%QN-NH2
878
2144.13
1073.07
1073.64

141
Ac-%r8SQQTFS%LWRLLAibQN-NH2
879
2040.15
1021.08
1021.13

142
Ac-LTF%r8HYWAQL%S-NH2
880
1599.88
800.94
801.09

143
Ac-TSF%r8QYWNLL%P-NH2
881
1602.88
802.44
802.58

147
Ac-LTFEHYWAQLTS-NH2
882
1535.74
768.87
769.5

152
Ac-F$er8AY6clWEAc3cL$e-NH2
883
1277.63
639.82
1278.71

153
Ac-AF$r8AAWALA$A-NH2
884
1277.63
639.82
1277.84

154
Ac-TF$r8AAWRLA$Q-NH2
885
1395.80
698.90
699.04

155
Pr-TF$r8AAWRLA$Q-NH2
886
1409.82
705.91
706.04

156
Ac-LTF$er8HYWAQL$eS-NH2
887
1597.87
799.94
800.44

159
Ac-CCPGCCBaQSQQTF$r8NLWRLL$QN-
888
2745.30
1373.65
1372.99

NH2

160
Ac-CCPGCCBaQSQQTA$r8NLWRLL$QN-
889
2669.27
1335.64
1336.09

NH2

161
Ac-CCPGCCBaNlePRF$r8NYWRLL$QN-
890
2589.26
1295.63
1296.2

NH2

162
Ac-LTF$/r8HYWAQL$/S-NH2
891
1625.90
813.95
814.18

163
Ac-F%r8HY6clWRAc3cL%-NH2
892
1372.72
687.36
687.59

164
Ac-QTF%r8HWWSQL%S-NH2
893
1653.87
827.94
827.94

165
Ac-LTA$r8HYWRQL$S-NH2
894
1606.90
804.45
804.66

166
Ac-Q$r8QQTFSN$WRLLAibQN-NH2
895
2080.12
1041.06
1041.61

167
Ac-QSQQ$r8FSNLWR$LAibQN-NH2
896
2066.11
1034.06
1034.58

168
Ac-F$r8AYWEAc3cL$A-NH2
897
1314.70
658.35
1315.88

169
Ac-F$r8AYWEAc3cL$S-NH2
898
1330.70
666.35
1331.87

170
Ac-F$r8AYWEAc3cL$Q-NH2
899
1371.72
686.86
1372.72

171
Ac-F$r8AYWEAibL$S-NH2
900
1332.71
667.36
1334.83

172
Ac-F$r8AYWEAL$S-NH2
901
1318.70
660.35
1319.73

173
Ac-F$r8AYWEQL$S-NH2
902
1375.72
688.86
1377.53

174
Ac-F$r8HYWEQL$S-NH2
903
1441.74
721.87
1443.48

175
Ac-F$r8HYWAQL$S-NH2
904
1383.73
692.87
1385.38

176
Ac-F$r8HYWAAc3cL$S-NH2
905
1338.71
670.36
1340.82

177
Ac-F$r8HYWRAc3cL$S-NH2
906
1423.78
712.89
713.04

178
Ac-F$r8AYWEAc3cL#A-NH2
907
1300.69
651.35
1302.78

179
Ac-NlePTF%r8NYWRLL%QN-NH2
908
1899.08
950.54
950.56

180
Ac-TF$r8AAWRAL$Q-NH2
909
1395.80
698.90
699.13

181
Ac-TSF%r8HYWAQL%S-NH2
910
1573.83
787.92
787.98

184
Ac-F%r8AY6clWEAc3cL%A-NH2
911
1350.68
676.34
676.91

185
Ac-LTF$r8HYWAQI$S-NH2
912
1597.87
799.94
800.07

186
Ac-LTF$r8HYWAQNle$S-NH2
913
1597.87
799.94
800.07

187
Ac-LTF$r8HYWAQL$A-NH2
914
1581.87
791.94
792.45

188
Ac-LTF$r8HYWAQL$Abu-NH2
915
1595.89
798.95
799.03

189
Ac-LTF$r8HYWAbuQL$S-NH2
916
1611.88
806.94
807.47

190
Ac-LTF$er8AYWAQUeS-NH2
917
1531.84
766.92
766.96

191
Ac-LAF$r8HYWAQL$S-NH2
918
1567.86
784.93
785.49

192
Ac-LAF$r8AYWAQL$S-NH2
919
1501.83
751.92
752.01

193
Ac-LTF$er8AYWAQL$eA-NH2
920
1515.85
758.93
758.97

194
Ac-LAF$r8AYWAQL$A-NH2
921
1485.84
743.92
744.05

195
Ac-LTF$r8NLWANleL$Q-NH2
922
1550.92
776.46
776.61

196
Ac-LTF$r8NLWANleL$A-NH2
923
1493.90
747.95
1495.6

197
Ac-LTF$r8ALWANleL$Q-NH2
924
1507.92
754.96
755

198
Ac-LAF$r8NLWANleL$Q-NH2
925
1520.91
761.46
761.96

199
Ac-LAF$r8ALWANleL$A-NH2
926
1420.89
711.45
1421.74

200
Ac-A$r8AYWEAc3cL$A-NH2
927
1238.67
620.34
1239.65

201
Ac-F$r8AYWEAc3cL$AA-NH2
928
1385.74
693.87
1386.64

202
Ac-F$r8AYWEAc3cL$Abu-NH2
929
1328.72
665.36
1330.17

203
Ac-F$r8AYWEAc3cL$Nle-NH2
930
1356.75
679.38
1358.22

204
Ac-F$r5AYWEAc3cL$s8A-NH2
931
1314.70
658.35
1315.51

205
Ac-F$AYWEAc3cL$r8A-NH2
932
1314.70
658.35
1315.66

206
Ac-F$r8AYWEAc3cI$A-NH2
933
1314.70
658.35
1316.18

207
Ac-F$r8AYWEAc3cNle$A-NH2
934
1314.70
658.35
1315.66

208
Ac-F$r8AYWEAmlL$A-NH2
935
1358.76
680.38
1360.21

209
Ac-F$r8AYWENleL$A-NH2
936
1344.75
673.38
1345.71

210
Ac-F$r8AYWQAc3cL$A-NH2
937
1313.72
657.86
1314.7

211
Ac-F$r8AYWAAc3cL$A-NH2
938
1256.70
629.35
1257.56

212
Ac-F$r8AYWAbuAc3cL$A-NH2
939
1270.71
636.36
1272.14

213
Ac-F$r8AYWNleAc3cL$A-NH2
940
1298.74
650.37
1299.67

214
Ac-F$r8AbuYWEAc3cL$A-NH2
941
1328.72
665.36
1329.65

215
Ac-F$r8NleYWEAc3cL$A-NH2
942
1356.75
679.38
1358.66

216
5-FAM-BaLTFEHYWAQLTS-NH2
943
1922.82
962.41
962.87

217
5-FAM-BaLTF%r8HYWAQL%S-NH2
944
1986.96
994.48
994.97

218
Ac-LTF$r8HYWAQhL$S-NH2
945
1611.88
806.94
807

219
Ac-LTF$r8HYWAQTle$S-NH2
946
1597.87
799.94
799.97

220
Ac-LTF$r8HYWAQAdm$S-NH2
947
1675.91
838.96
839.09

221
Ac-LTF$r8HYWAQhCha$S-NH2
948
1651.91
826.96
826.98

222
Ac-LTF$r8HYWAQCha$S-NH2
949
1637.90
819.95
820.02

223
Ac-LTF$r8HYWAc6cQL$S-NH2
950
1651.91
826.96
826.98

224
Ac-LTF$r8HYWAc5cQL$S-NH2
951
1637.90
819.95
820.02

225
Ac-LThF$r8HYWAQL$S-NH2
952
1611.88
806.94
807

226
Ac-LTIg1$r8HYWAQL$S-NH2
953
1625.90
813.95
812.99

227
Ac-LTF$r8HYWAQChg$S-NH2
954
1623.88
812.94
812.99

228
Ac-LTF$r8HYWAQF$S-NH2
955
1631.85
816.93
816.99

229
Ac-LTF$r8HYWAQIg1$S-NH2
956
1659.88
830.94
829.94

230
Ac-LTF$r8HYWAQCba$S-NH2
957
1609.87
805.94
805.96

231
Ac-LTF$r8HYWAQCpg$S-NH2
958
1609.87
805.94
805.96

232
Ac-LTF$r8HhYWAQL$S-NH2
959
1611.88
806.94
807

233
Ac-F$r8AYWEAc3chL$A-NH2
960
1328.72
665.36
665.43

234
Ac-F$r8AYWEAc3cT1e$A-NH2
961
1314.70
658.35
1315.62

235
Ac-F$r8AYWEAc3cAdm$A-NH2
962
1392.75
697.38
697.47

236
Ac-F$r8AYWEAc3chCha$A-NH2
963
1368.75
685.38
685.34

237
Ac-F$r8AYWEAc3cCha$A-NH2
964
1354.73
678.37
678.38

238
Ac-F$r8AYWEAc6cL$A-NH2
965
1356.75
679.38
679.42

239
Ac-F$r8AYWEAc5cL$A-NH2
966
1342.73
672.37
672.46

240
Ac-hF$r8AYWEAc3cL$A-NH2
967
1328.72
665.36
665.43

241
Ac-Ig1$r8AYWEAc3cL$A-NH2
968
1342.73
672.37
671.5

243
Ac-F$r8AYWEAc3cF$A-NH2
969
1348.69
675.35
675.35

244
Ac-F$r8AYWEAc3cIg1$A-NH2
970
1376.72
689.36
688.37

245
Ac-F$r8AYWEAc3cCba$A-NH2
971
1326.70
664.35
664.47

246
Ac-F$r8AYWEAc3cCpg$A-NH2
972
1326.70
664.35
664.39

247
Ac-F$r8AhYWEAc3cL$A-NH2
973
1328.72
665.36
665.43

248
Ac-F$r8AYWEAc3cL$Q-NH2
974
1371.72
686.86
1372.87

249
Ac-F$r8AYWEAibL$A-NH2
975
1316.72
659.36
1318.18

250
Ac-F$r8AYWEAL$A-NH2
976
1302.70
652.35
1303.75

251
Ac-LAF$r8AYWAAL$A-NH2
977
1428.82
715.41
715.49

252
Ac-LTF$r8HYWAAc3cL$S-NH2
978
1552.84
777.42
777.5

253
Ac-NleTF$r8HYWAQL$S-NH2
979
1597.87
799.94
800.04

254
Ac-VTF$r8HYWAQL$S-NH2
980
1583.85
792.93
793.04

255
Ac-FTF$r8HYWAQL$S-NH2
981
1631.85
816.93
817.02

256
Ac-WTF$r8HYWAQL$S-NH2
982
1670.86
836.43
836.85

257
Ac-RTF$r8HYWAQL$S-NH2
983
1640.88
821.44
821.9

258
Ac-KTF$r8HYWAQL$S-NH2
984
1612.88
807.44
807.91

259
Ac-LNleF$r8HYWAQL$S-NH2
985
1609.90
805.95
806.43

260
Ac-LVF$r8HYWAQL$S-NH2
986
1595.89
798.95
798.93

261
Ac-LFF$r8HYWAQL$S-NH2
987
1643.89
822.95
823.38

262
Ac-LWF$r8HYWAQL$S-NH2
988
1682.90
842.45
842.55

263
Ac-LRF$r8HYWAQL$S-NH2
989
1652.92
827.46
827.52

264
Ac-LKF$r8HYWAQL$S-NH2
990
1624.91
813.46
813.51

265
Ac-LTF$r8NleYWAQL$S-NH2
991
1573.89
787.95
788.05

266
Ac-LTF$r8VYWAQL$S-NH2
992
1559.88
780.94
780.98

267
Ac-LTF$r8FYWAQL$S-NH2
993
1607.88
804.94
805.32

268
Ac-LTF$r8WYWAQL$S-NH2
994
1646.89
824.45
824.86

269
Ac-LTF$r8RYWAQL$S-NH2
995
1616.91
809.46
809.51

270
Ac-LTF$r8KYWAQL$S-NH2
996
1588.90
795.45
795.48

271
Ac-LTF$r8HNleWAQL$S-NH2
997
1547.89
774.95
774.98

272
Ac-LTF$r8HVWAQL$S-NH2
998
1533.87
767.94
767.95

273
Ac-LTF$r8HFVVAQL$S-NH2
999
1581.87
791.94
792.3

274
Ac-LTF$r8HWWAQL$S-NH2
1000
1620.88
811.44
811.54

275
Ac-LTF$r8HRWAQL$S-NH2
1001
1590.90
796.45
796.52

276
Ac-LTF$r8HKWAQL$S-NH2
1002
1562.90
782.45
782.53

277
Ac-LTF$r8HYWNleQL$S-NH2
1003
1639.91
820.96
820.98

278
Ac-LTF$r8HYWVQL$S-NH2
1004
1625.90
813.95
814.03

279
Ac-LTF$r8HYWFQL$S-NH2
1005
1673.90
837.95
838.03

280
Ac-LTF$r8HYWWQL$S-NH2
1006
1712.91
857.46
857.5

281
Ac-LTF$r8HYWKQL$S-NH2
1007
1654.92
828.46
828.49

282
Ac-LTF$r8HYWANleL$S-NH2
1008
1582.89
792.45
792.52

283
Ac-LTF$r8HYWAVL$S-NH2
1009
1568.88
785.44
785.49

284
Ac-LTF$r8HYWAFL$S-NH2
1010
1616.88
809.44
809.47

285
Ac-LTF$r8HYWAWL$S-NH2
1011
1655.89
828.95
829

286
Ac-LTF$r8HYWARL$S-NH2
1012
1625.91
813.96
813.98

287
Ac-LTF$r8HYWAQL$Nle-NH2
1013
1623.92
812.96
813.39

288
Ac-LTF$r8HYWAQL$V-NH2
1014
1609.90
805.95
805.99

289
Ac-LTF$r8HYWAQL$F-NH2
1015
1657.90
829.95
830.26

290
Ac-LTF$r8HYWAQL$W-NH2
1016
1696.91
849.46
849.5

291
Ac-LTF$r8HYWAQL$R-NH2
1017
1666.94
834.47
834.56

292
Ac-LTF$r8HYWAQL$K-NH2
1018
1638.93
820.47
820.49

293
Ac-Q$r8QQTFSN$WRLLAibQN-NH2
1019
2080.12
1041.06
1041.54

294
Ac-QSQQ$r8FSNLWR$LAibQN-NH2
1020
2066.11
1034.06
1034.58

295
Ac-LT2Pal$r8HYWAQL$S-NH2
1021
1598.86
800.43
800.49

296
Ac-LT3Pal$r8HYWAQL$S-NH2
1022
1598.86
800.43
800.49

297
Ac-LT4Pal$r8HYWAQL$S-NH2
1023
1598.86
800.43
800.49

298
Ac-LTF2CF3$r8HYWAQL$S-NH2
1024
1665.85
833.93
834.01

299
Ac-LTF2CN$r8HYWAQL$S-NH2
1025
1622.86
812.43
812.47

300
Ac-LTF2Me$r8HYWAQL$S-NH2
1026
1611.88
806.94
807

301
Ac-LTF3Cl$r8HYWAQL$S-NH2
1027
1631.83
816.92
816.99

302
Ac-LTF4CF3$r8HYWAQL$S-NH2
1028
1665.85
833.93
833.94

303
Ac-LTF4tBu$r8HYWAQL$S-NH2
1029
1653.93
827.97
828.02

304
Ac-LTF5F$r8HYWAQL$S-NH2
1030
1687.82
844.91
844.96

305
Ac-LTF$r8HY3BthAAQL$S-NH2
1031
1614.83
808.42
808.48

306
Ac-LTF2Br$r8HYWAQL$S-NH2
1032
1675.78
838.89
838.97

307
Ac-LTF4Br$r8HYWAQL$S-NH2
1033
1675.78
838.89
839.86

308
Ac-LTF2Cl$r8HYWAQL$S-NH2
1034
1631.83
816.92
816.99

309
Ac-LTF4Cl$r8HYWAQL$S-NH2
1035
1631.83
816.92
817.36

310
Ac-LTF3CN$r8HYWAQL$S-NH2
1036
1622.86
812.43
812.47

311
Ac-LTF4CN$r8HYWAQL$S-NH2
1037
1622.86
812.43
812.47

312
Ac-LTF34Cl2$r8HYWAQL$S-NH2
1038
1665.79
833.90
833.94

313
Ac-LTF34F2$r8HYWAQL$S-NH2
1039
1633.85
817.93
817.95

314
Ac-LTF35F2$r8HYWAQL$S-NH2
1040
1633.85
817.93
817.95

315
Ac-LTDip$r8HYWAQL$S-NH2
1041
1673.90
837.95
838.01

316
Ac-LTF2F$r8HYWAQL$S-NH2
1042
1615.86
808.93
809

317
Ac-LTF3F$r8HYWAQL$S-NH2
1043
1615.86
808.93
809

318
Ac-LTF4F$r8HYWAQL$S-NH2
1044
1615.86
808.93
809

319
Ac-LTF41$r8HYWAQL$S-NH2
1045
1723.76
862.88
862.94

320
Ac-LTF3Me$r8HYWAQL$S-NH2
1046
1611.88
806.94
807.07

321
Ac-LTF4Me$r8HYWAQL$S-NH2
1047
1611.88
806.94
807

322
Ac-LT1Nal$r8HYWAQL$S-NH2
1048
1647.88
824.94
824.98

323
Ac-LT2Nal$r8HYWAQL$S-NH2
1049
1647.88
824.94
825.06

324
Ac-LTF3CF3$r8HYWAQL$S-NH2
1050
1665.85
833.93
834.01

325
Ac-LTF4NO2$r8HYWAQL$S-NH2
1051
1642.85
822.43
822.46

326
Ac-LTF3NO2$r8HYWAQL$S-NH2
1052
1642.85
822.43
822.46

327
Ac-LTF$r82ThiYWAQL$S-NH2
1053
1613.83
807.92
807.96

328
Ac-LTF$r8HBipWAQL$S-NH2
1054
1657.90
829.95
830.01

329
Ac-LTF$r8HF4tBuWAQL$S-NH2
1055
1637.93
819.97
820.02

330
Ac-LTF$r8HF4CF3WAQL$S-NH2
1056
1649.86
825.93
826.02

331
Ac-LTF$r8HF4ClWAQL$S-NH2
1057
1615.83
808.92
809.37

332
Ac-LTF$r8HF4MeWAQL$S-NH2
1058
1595.89
798.95
799.01

333
Ac-LTF$r8HF4BrWAQL$S-NH2
1059
1659.78
830.89
830.98

334
Ac-LTF$r8HF4CNWAQL$S-NH2
1060
1606.87
804.44
804.56

335
Ac-LTF$r8HF4NO2WAQL$S-NH2
1061
1626.86
814.43
814.55

336
Ac-LTF$r8H1Na1WAQL$S-NH2
1062
1631.89
816.95
817.06

337
Ac-LTF$r8H2Na1WAQL$S-NH2
1063
1631.89
816.95
816.99

338
Ac-LTF$r8HWAQL$S-NH2
1064
1434.80
718.40
718.49

339
Ac-LTF$r8HY1NalAQL$S-NH2
1065
1608.87
805.44
805.52

340
Ac-LTF$r8HY2NalAQL$S-NH2
1066
1608.87
805.44
805.52

341
Ac-LTF$r8HYWAQI$S-NH2
1067
1597.87
799.94
800.07

342
Ac-LTF$r8HYWAQNle$S-NH2
1068
1597.87
799.94
800.44

343
Ac-LTF$er8HYWAQL$eA-NH2
1069
1581.87
791.94
791.98

344
Ac-LTF$r8HYWAQL$Abu-NH2
1070
1595.89
798.95
799.03

345
Ac-LTF$r8HYWAbuQL$S-NH2
1071
1611.88
806.94
804.47

346
Ac-LAF$r8HYWAQL$S-NH2
1072
1567.86
784.93
785.49

347
Ac-LTF$r8NLWANleL$Q-NH2
1073
1550.92
776.46
777.5

348
Ac-LTF$r8ALWANleL$Q-NH2
1074
1507.92
754.96
755.52

349
Ac-LAF$r8NLWANleL$Q-NH2
1075
1520.91
761.46
762.48

350
Ac-F$r8AYWAAc3cL$A-NH2
1076
1256.70
629.35
1257.56

351
Ac-LTF$r8AYWAAL$S-NH2
1077
1474.82
738.41
738.55

352
Ac-LVF$r8AYWAQL$S-NH2
1078
1529.87
765.94
766

353
Ac-LTF$r8AYWAbuQL$S-NH2
1079
1545.86
773.93
773.92

354
Ac-LTF$r8AYWNleQL$S-NH2
1080
1573.89
787.95
788.17

355
Ac-LTF$r8AbuYWAQL$S-NH2
1081
1545.86
773.93
773.99

356
Ac-LTF$r8AYWHQL$S-NH2
1082
1597.87
799.94
799.97

357
Ac-LTF$r8AYWKQL$S-NH2
1083
1588.90
795.45
795.53

358
Ac-LTF$r8AYWOQL$S-NH2
1084
1574.89
788.45
788.5

359
Ac-LTF$r8AYWRQL$S-NH2
1085
1616.91
809.46
809.51

360
Ac-LTF$r8AYWSQL$S-NH2
1086
1547.84
774.92
774.96

361
Ac-LTF$r8AYWRAL$S-NH2
1087
1559.89
780.95
780.95

362
Ac-LTF$r8AYWRQL$A-NH2
1088
1600.91
801.46
801.52

363
Ac-LTF$r8AYWRAL$A-NH2
1089
1543.89
772.95
773.03

364
Ac-LTF$r5HYWAQL$s8S-NH2
1090
1597.87
799.94
799.97

365
Ac-LTF$HYWAQL$r8S-NH2
1091
1597.87
799.94
799.97

366
Ac-LTF$r8HYWAAL$S-NH2
1092
1540.84
771.42
771.48

367
Ac-LTF$r8HYWAAbuL$S-NH2
1093
1554.86
778.43
778.51

368
Ac-LTF$r8HYWALL$S-NH2
1094
1582.89
792.45
792.49

369
Ac-F$r8AYWHAL$A-NH2
1095
1310.72
656.36
656.4

370
Ac-F$r8AYWAAL$A-NH2
1096
1244.70
623.35
1245.61

371
Ac-F$r8AYWSAL$A-NH2
1097
1260.69
631.35
1261.6

372
Ac-F$r8AYWRAL$A-NH2
1098
1329.76
665.88
1330.72

373
Ac-F$r8AYWKAL$A-NH2
1099
1301.75
651.88
1302.67

374
Ac-F$r8AYWOAL$A-NH2
1100
1287.74
644.87
1289.13

375
Ac-F$r8VYWEAc3cL$A-NH2
1101
1342.73
672.37
1343.67

376
Ac-F$r8FYWEAc3cL$A-NH2
1102
1390.73
696.37
1392.14

377
Ac-F$r8WYWEAc3cL$A-NH2
1103
1429.74
715.87
1431.44

378
Ac-F$r8RYWEAc3cL$A-NH2
1104
1399.77
700.89
700.95

379
Ac-F$r8KYWEAc3cL$A-NH2
1105
1371.76
686.88
686.97

380
Ac-F$r8ANleWEAc3cL$A-NH2
1106
1264.72
633.36
1265.59

381
Ac-F$r8AVWEAc3cL$A-NH2
1107
1250.71
626.36
1252.2

382
Ac-F$r8AFWEAc3cL$A-NH2
1108
1298.71
650.36
1299.64

383
Ac-F$r8AWWEAc3cL$A-NH2
1109
1337.72
669.86
1338.64

384
Ac-F$r8ARWEAc3cL$A-NH2
1110
1307.74
654.87
655

385
Ac-F$r8AKWEAc3cL$A-NH2
1111
1279.73
640.87
641.01

386
Ac-F$r8AYWVAc3cL$A-NH2
1112
1284.73
643.37
643.38

387
Ac-F$r8AYWFAc3cL$A-NH2
1113
1332.73
667.37
667.43

388
Ac-F$r8AYWWAc3cL$A-NH2
1114
1371.74
686.87
686.97

389
Ac-F$r8AYWRAc3cL$A-NH2
1115
1341.76
671.88
671.94

390
Ac-F$r8AYWKAc3cL$A-NH2
1116
1313.75
657.88
657.88

391
Ac-F$r8AYWEVL$A-NH2
1117
1330.73
666.37
666.47

392
Ac-F$r8AYWEFL$A-NH2
1118
1378.73
690.37
690.44

393
Ac-F$r8AYWEWL$A-NH2
1119
1417.74
709.87
709.91

394
Ac-F$r8AYWERL$A-NH2
1120
1387.77
694.89
1388.66

395
Ac-F$r8AYWEKL$A-NH2
1121
1359.76
680.88
1361.21

396
Ac-F$r8AYWEAc3cL$V-NH2
1122
1342.73
672.37
1343.59

397
Ac-F$r8AYWEAc3cL$F-NH2
1123
1390.73
696.37
1392.58

398
Ac-F$r8AYWEAc3cL$W-NH2
1124
1429.74
715.87
1431.29

399
Ac-F$r8AYWEAc3cL$R-NH2
1125
1399.77
700.89
700.95

400
Ac-F$r8AYWEAc3cL$K-NH2
1126
1371.76
686.88
686.97

401
Ac-F$r8AYWEAc3cL$AV-NH2
1127
1413.77
707.89
707.91

402
Ac-F$r8AYWEAc3cL$AF-NH2
1128
1461.77
731.89
731.96

403
Ac-F$r8AYWEAc3cL$AW-NH2
1129
1500.78
751.39
751.5

404
Ac-F$r8AYWEAc3cL$AR-NH2
1130
1470.80
736.40
736.47

405
Ac-F$r8AYWEAc3cL$AK-NH2
1131
1442.80
722.40
722.41

406
Ac-F$r8AYWEAc3cL$AH-NH2
1132
1451.76
726.88
726.93

407
Ac-LTF2NO2$r8HYWAQL$S-NH2
1133
1642.85
822.43
822.54

408
Ac-LTA$r8HYAAQL$S-NH2
1134
1406.79
704.40
704.5

409
Ac-LTF$r8HYAAQL$S-NH2
1135
1482.82
742.41
742.47

410
Ac-QSQQTF$r8NLWALL$AN-NH2
1136
1966.07
984.04
984.38

411
Ac-QAibQQTF$r8NLWALL$AN-NH2
1137
1964.09
983.05
983.42

412
Ac-QAibQQTF$r8ALWALL$AN-NH2
1138
1921.08
961.54
961.59

413
Ac-AAAATF$r8AAWAAL$AA-NH2
1139
1608.90
805.45
805.52

414
Ac-F$r8AAWRAL$Q-NH2
1140
1294.76
648.38
648.48

415
Ac-TF$r8AAWAAL$Q-NH2
1141
1310.74
656.37
1311.62

416
Ac-TF$r8AAWRAL$A-NH2
1142
1338.78
670.39
670.46

417
Ac-VF$r8AAWRAL$Q-NH2
1143
1393.82
697.91
697.99

418
Ac-AF$r8AAWAAL$A-NH2
1144
1223.71
612.86
1224.67

420
Ac-TF$r8AAWKAL$Q-NH2
1145
1367.80
684.90
684.97

421
Ac-TF$r8AAWOAL$Q-NH2
1146
1353.78
677.89
678.01

422
Ac-TF$r8AAWSAL$Q-NH2
1147
1326.73
664.37
664.47

423
Ac-LTF$r8AAWRAL$Q-NH2
1148
1508.89
755.45
755.49

424
Ac-F$r8AYWAQL$A-NH2
1149
1301.72
651.86
651.96

425
Ac-F$r8AWWAAL$A-NH2
1150
1267.71
634.86
634.87

426
Ac-F$r8AWWAQL$A-NH2
1151
1324.73
663.37
663.43

427
Ac-F$r8AYWEAL$-NH2
1152
1231.66
616.83
1232.93

428
Ac-F$r8AYWAAL$-NH2
1153
1173.66
587.83
1175.09

429
Ac-F$r8AYWKAL$-NH2
1154
1230.72
616.36
616.44

430
Ac-F$r8AYWOAL$-NH2
1155
1216.70
609.35
609.48

431
Ac-F$r8AYWQAL$-NH2
1156
1230.68
616.34
616.44

432
Ac-F$r8AYWAQL$-NH2
1157
1230.68
616.34
616.37

433
Ac-F$r8HYWDQL$S-NH2
1158
1427.72
714.86
714.86

434
Ac-F$r8HFVVEQL$S-NH2
1159
1425.74
713.87
713.98

435
Ac-F$r8AYWHQL$S-NH2
1160
1383.73
692.87
692.96

436
Ac-F$r8AYWKQL$S-NH2
1161
1374.77
688.39
688.45

437
Ac-F$r8AYWOQL$S-NH2
1162
1360.75
681.38
681.49

438
Ac-F$r8HYWSQL$S-NH2
1163
1399.73
700.87
700.95

439
Ac-F$r8HWWEQL$S-NH2
1164
1464.76
733.38
733.44

440
Ac-F$r8HWWAQL$S-NH2
1165
1406.75
704.38
704.43

441
Ac-F$r8AWWHQL$S-NH2
1166
1406.75
704.38
704.43

442
Ac-F$r8AWWKQL$S-NH2
1167
1397.79
699.90
699.92

443
Ac-F$r8AWWOQL$S-NH2
1168
1383.77
692.89
692.96

444
Ac-F$r8HWWSQL$S-NH2
1169
1422.75
712.38
712.42

445
Ac-LTF$r8NYWANleL$Q-NH2
1170
1600.90
801.45
801.52

446
Ac-LTF$r8NLWAQL$Q-NH2
1171
1565.90
783.95
784.06

447
Ac-LTF$r8NYWANleL$A-NH2
1172
1543.88
772.94
773.03

448
Ac-LTF$r8NLWAQL$A-NH2
1173
1508.88
755.44
755.49

449
Ac-LTF$r8AYWANleL$Q-NH2
1174
1557.90
779.95
780.06

450
Ac-LTF$r8ALWAQL$Q-NH2
1175
1522.89
762.45
762.45

451
Ac-LAF$r8NYWANleL$Q-NH2
1176
1570.89
786.45
786.5

452
Ac-LAF$r8NLWAQL$Q-NH2
1177
1535.89
768.95
769.03

453
Ac-LAF$r8AYWANleL$A-NH2
1178
1470.86
736.43
736.47

454
Ac-LAF$r8ALWAQL$A-NH2
1179
1435.86
718.93
719.01

455
Ac-LAF$r8AYWAAL$A-NH2
1180
1428.82
715.41
715.41

456
Ac-F$r8AYWEAc3cL$AAib-NH2
1181
1399.75
700.88
700.95

457
Ac-F$r8AYWAQL$AA-NH2
1182
1372.75
687.38
687.78

458
Ac-F$r8AYWAAc3cL$AA-NH2
1183
1327.73
664.87
664.84

459
Ac-F$r8AYWSAc3cL$AA-NH2
1184
1343.73
672.87
672.9

460
Ac-F$r8AYWEAc3cL$AS-NH2
1185
1401.73
701.87
701.84

461
Ac-F$r8AYWEAc3cL$AT-NH2
1186
1415.75
708.88
708.87

462
Ac-F$r8AYWEAc3cL$AL-NH2
1187
1427.79
714.90
714.94

463
Ac-F$r8AYWEAc3cL$AQ-NH2
1188
1442.76
722.38
722.41

464
Ac-F$r8AFWEAc3cL$AA-NH2
1189
1369.74
685.87
685.93

465
Ac-F$r8AWWEAc3cL$AA-NH2
1190
1408.75
705.38
705.39

466
Ac-F$r8AYWEAc3cL$SA-NH2
1191
1401.73
701.87
701.99

467
Ac-F$r8AYWEAL$AA-NH2
1192
1373.74
687.87
687.93

468
Ac-F$r8AYWENleL$AA-NH2
1193
1415.79
708.90
708.94

469
Ac-F$r8AYWEAc3cL$AbuA-NH2
1194
1399.75
700.88
700.95

470
Ac-F$r8AYWEAc3cL$NleA-NH2
1195
1427.79
714.90
714.86

471
Ac-F$r8AYWEAibL$NleA-NH2
1196
1429.80
715.90
715.97

472
Ac-F$r8AYWEAL$NleA-NH2
1197
1415.79
708.90
708.94

473
Ac-F$r8AYWENleL$NleA-NH2
1198
1457.83
729.92
729.96

474
Ac-F$r8AYWEAibL$Abu-NH2
1199
1330.73
666.37
666.39

475
Ac-F$r8AYWENleL$Abu-NH2
1200
1358.76
680.38
680.39

476
Ac-F$r8AYWEAL$Abu-NH2
1201
1316.72
659.36
659.36

477
Ac-LTF$r8AFWAQL$S-NH2
1202
1515.85
758.93
759.12

478
Ac-LTF$r8AWWAQL$S-NH2
1203
1554.86
778.43
778.51

479
Ac-LTF$r8AYWAQI$S-NH2
1204
1531.84
766.92
766.96

480
Ac-LTF$r8AYWAQNle$S-NH2
1205
1531.84
766.92
766.96

481
Ac-LTF$r8AYWAQL$SA-NH2
1206
1602.88
802.44
802.48

482
Ac-LTF$r8AWWAQL$A-NH2
1207
1538.87
770.44
770.89

483
Ac-LTF$r8AYWAQI$A-NH2
1208
1515.85
758.93
759.42

484
Ac-LTF$r8AYWAQNle$A-NH2
1209
1515.85
758.93
759.42

485
Ac-LTF$r8AYWAQL$AA-NH2
1210
1586.89
794.45
794.94

486
Ac-LTF$r8HWWAQL$S-NH2
1211
1620.88
811.44
811.47

487
Ac-LTF$r8HRWAQL$S-NH2
1212
1590.90
796.45
796.52

488
Ac-LTF$r8HKWAQL$S-NH2
1213
1562.90
782.45
782.53

489
Ac-LTF$r8HYWAQL$W-NH2
1214
1696.91
849.46
849.5

491
Ac-F$r8AYWAbuAL$A-NH2
1215
1258.71
630.36
630.5

492
Ac-F$r8AbuYWEAL$A-NH2
1216
1316.72
659.36
659.51

493
Ac-NlePRF%r8NYWRLL%QN-NH2
1217
1954.13
978.07
978.54

494
Ac-TSF%r8HYWAQL%S-NH2
1218
1573.83
787.92
787.98

495
Ac-LTF%r8AYWAQL%S-NH2
1219
1533.86
767.93
768

496
Ac-HTF$r8HYWAQL$S-NH2
1220
1621.84
811.92
811.96

497
Ac-LHF$r8HYWAQL$S-NH2
1221
1633.88
817.94
818.02

498
Ac-LTF$r8HHWAQL$S-NH2
1222
1571.86
786.93
786.94

499
Ac-LTF$r8HYWHQL$S-NH2
1223
1663.89
832.95
832.38

500
Ac-LTF$r8HYWAHL$S-NH2
1224
1606.87
804.44
804.48

501
Ac-LTF$r8HYWAQL$H-NH2
1225
1647.89
824.95
824.98

502
Ac-LTF$r8HYWAQL$S-NHPr
1226
1639.91
820.96
820.98

503
Ac-LTF$r8HYWAQL$S-NHsBu
1227
1653.93
827.97
828.02

504
Ac-LTF$r8HYWAQL$S-NHiBu
1228
1653.93
827.97
828.02

505
Ac-LTF$r8HYWAQL$S-NHBn
1229
1687.91
844.96
844.44

506
Ac-LTF$r8HYWAQL$S-NHPe
1230
1700.92
851.46
851.99

507
Ac-LTF$r8HYWAQL$S-NHChx
1231
1679.94
840.97
841.04

508
Ac-ETF$r8AYWAQL$S-NH2
1232
1547.80
774.90
774.96

509
Ac-STF$r8AYWAQL$S-NH2
1233
1505.79
753.90
753.94

510
Ac-LEF$r8AYWAQL$S-NH2
1234
1559.84
780.92
781.25

511
Ac-LSF$r8AYWAQL$S-NH2
1235
1517.83
759.92
759.93

512
Ac-LTF$r8EYWAQL$S-NH2
1236
1589.85
795.93
795.97

513
Ac-LTF$r8SYWAQL$S-NH2
1237
1547.84
774.92
774.96

514
Ac-LTF$r8AYWEQL$S-NH2
1238
1589.85
795.93
795.9

515
Ac-LTF$r8AYWAEL$S-NH2
1239
1532.83
767.42
766.96

516
Ac-LTF$r8AYWASL$S-NH2
1240
1490.82
746.41
746.46

517
Ac-LTF$r8AYWAQL$E-NH2
1241
1573.85
787.93
787.98

518
Ac-LTF2CN$r8HYWAQL$S-NH2
1242
1622.86
812.43
812.47

519
Ac-LTF3Cl$r8HYWAQL$S-NH2
1243
1631.83
816.92
816.99

520
Ac-LTDip$r8HYWAQL$S-NH2
1244
1673.90
837.95
838.01

521
Ac-LTF$r8HYWAQT1e$S-NH2
1245
1597.87
799.94
800.04

522
Ac-F$r8AY6clWEAL$A-NH2
1246
1336.66
669.33
1338.56

523
Ac-F$r8AYd16brWEAL$A-NH2
1247
1380.61
691.31
692.2

524
Ac-F$r8AYd16fWEAL$A-NH2
1248
1320.69
661.35
1321.61

525
Ac-F$r8AYd14mWEAL$A-NH2
1249
1316.72
659.36
659.36

526
Ac-F$r8AYd15clWEAL$A-NH2
1250
1336.66
669.33
669.35

527
Ac-F$r8AYd17mWEAL$A-NH2
1251
1316.72
659.36
659.36

528
Ac-LTF%r8HYWAQL%A-NH2
1252
1583.89
792.95
793.01

529
Ac-LTF$r8HCouWAQL$S-NH2
1253
1679.87
840.94
841.38

530
Ac-LTFEHCouWAQLTS-NH2
1254
1617.75
809.88
809.96

531
Ac-LTA$r8HCouWAQL$S-NH2
1255
1603.84
802.92
803.36

532
Ac-F$r8AYWEAL$AbuA-NH2
1256
1387.75
694.88
694.88

533
Ac-F$r8AYWEA1$AA-NH2
1257
1373.74
687.87
687.93

534
Ac-F$r8AYWEANle$AA-NH2
1258
1373.74
687.87
687.93

535
Ac-F$r8AYWEAmlL$AA-NH2
1259
1429.80
715.90
715.97

536
Ac-F$r8AYWQAL$AA-NH2
1260
1372.75
687.38
687.48

537
Ac-F$r8AYWAAL$AA-NH2
1261
1315.73
658.87
658.92

538
Ac-F$r8AYWAbuAL$AA-NH2
1262
1329.75
665.88
665.95

539
Ac-F$r8AYWNleAL$AA-NH2
1263
1357.78
679.89
679.94

540
Ac-F$r8AbuYWEAL$AA-NH2
1264
1387.75
694.88
694.96

541
Ac-F$r8NleYWEAL$AA-NH2
1265
1415.79
708.90
708.94

542
Ac-F$r8FYWEAL$AA-NH2
1266
1449.77
725.89
725.97

543
Ac-LTF$r8HYWAQhL$S-NH2
1267
1611.88
806.94
807

544
Ac-LTF$r8HYWAQAdm$S-NH2
1268
1675.91
838.96
839.04

545
Ac-LTF$r8HYWAQIg1$S-NH2
1269
1659.88
830.94
829.94

546
Ac-F$r8AYWAQL$AA-NH2
1270
1372.75
687.38
687.48

547
Ac-LTF$r8ALWAQL$Q-NH2
1271
1522.89
762.45
762.52

548
Ac-F$r8AYWEAL$AA-NH2
1272
1373.74
687.87
687.93

549
Ac-F$r8AYWENleL$AA-NH2
1273
1415.79
708.90
708.94

550
Ac-F$r8AYWEAibL$Abu-NH2
1274
1330.73
666.37
666.39

551
Ac-F$r8AYWENleL$Abu-NH2
1275
1358.76
680.38
680.38

552
Ac-F$r8AYWEAL$Abu-NH2
1276
1316.72
659.36
659.36

553
Ac-F$r8AYWEAc3cL$AbuA-NH2
1277
1399.75
700.88
700.95

554
Ac-F$r8AYWEAc3cL$NleA-NH2
1278
1427.79
714.90
715.01

555
H-LTF$r8AYWAQL$S-NH2
1279
1489.83
745.92
745.95

556
mdPEG3-LTF$r8AYWAQL$S-NH2
1280
1679.92
840.96
840.97

557
mdPEG7-LTF$r8AYWAQL$S-NH2
1281
1856.02
929.01
929.03

558
Ac-F$r8ApmpEt6c1WEAL$A-NH2
1282
1470.71
736.36
788.17

559
Ac-LTF3Cl$r8AYWAQL$S-NH2
1283
1565.81
783.91
809.18

560
Ac-LTF3Cl$r8HYWAQL$A-NH2
1284
1615.83
808.92
875.24

561
Ac-LTF3Cl$r8HYWWQL$S-NH2
1285
1746.87
874.44
841.65

562
Ac-LTF3Cl$r8AYWWQL$S-NH2
1286
1680.85
841.43
824.63

563
Ac-LTF$r8AYWWQL$S-NH2
1287
1646.89
824.45
849.98

564
Ac-LTF$r8HYWWQL$A-NH2
1288
1696.91
849.46
816.67

565
Ac-LTF$r8AYWWQL$A-NH2
1289
1630.89
816.45
776.15

566
Ac-LTF4F$r8AYWAQL$S-NH2
1290
1549.83
775.92
776.15

567
Ac-LTF2F$r8AYWAQL$S-NH2
1291
1549.83
775.92
776.15

568
Ac-LTF3F$r8AYWAQL$S-NH2
1292
1549.83
775.92
785.12

569
Ac-LTF34F2$r8AYWAQL$S-NH2
1293
1567.83
784.92
785.12

570
Ac-LTF35F2$r8AYWAQL$S-NH2
1294
1567.83
784.92
1338.74

571
Ac-F3Cl$r8AYWEAL$A-NH2
1295
1336.66
669.33
705.28

572
Ac-F3Cl$r8AYWEAL$AA-NH2
1296
1407.70
704.85
680.11

573
Ac-F$r8AY6clWEAL$AA-NH2
1297
1407.70
704.85
736.83

574
Ac-F$r8AY6clWEAL$-NH2
1298
1265.63
633.82
784.1

575
Ac-LTF$r8HYWAQLSt/S-NH2
1299
16.03
9.02
826.98

576
Ac-LTF$r8HYWAQL$S-NHsBu
1300
1653.93
827.97
828.02

577
Ac-STF$r8AYWAQL$S-NH2
1301
1505.79
753.90
753.94

578
Ac-LTF$r8AYWAEL$S-NH2
1302
1532.83
767.42
767.41

579
Ac-LTF$r8AYWAQL$E-NH2
1303
1573.85
787.93
787.98

580
mdPEG3-LTF$r8AYWAQL$S-NH2
1304
1679.92
840.96
840.97

581
Ac-LTF$r8AYWAQhL$S-NH2
1305
1545.86
773.93
774.31

583
Ac-LTF$r8AYWAQCha$S-NH2
1306
1571.88
786.94
787.3

584
Ac-LTF$r8AYWAQChg$S-NH2
1307
1557.86
779.93
780.4

585
Ac-LTF$r8AYWAQCba$S-NH2
1308
1543.84
772.92
780.13

586
Ac-LTF$r8AYWAQF$S-NH2
1309
1565.83
783.92
784.2

587
Ac-LTF4F$r8HYWAQhL$S-NH2
1310
1629.87
815.94
815.36

588
Ac-LTF4F$r8HYWAQCha$S-NH2
1311
1655.89
828.95
828.39

589
Ac-LTF4F$r8HYWAQChg$S-NH2
1312
1641.87
821.94
821.35

590
Ac-LTF4F$r8HYWAQCba$S-NH2
1313
1627.86
814.93
814.32

591
Ac-LTF4F$r8AYWAQhL$S-NH2
1314
1563.85
782.93
782.36

592
Ac-LTF4F$r8AYWAQCha$S-NH2
1315
1589.87
795.94
795.38

593
Ac-LTF4F$r8AYWAQChg$S-NH2
1316
1575.85
788.93
788.35

594
Ac-LTF4F$r8AYWAQCba$S-NH2
1317
1561.83
781.92
781.39

595
Ac-LTF3C1$r8AYWAQhL$S-NH2
1318
1579.82
790.91
790.35

596
Ac-LTF3C1$r8AYWAQCha$S-NH2
1319
1605.84
803.92
803.67

597
Ac-LTF3C1$r8AYWAQChg$S-NH2
1320
1591.82
796.91
796.34

598
Ac-LTF3C1$r8AYWAQCba$S-NH2
1321
1577.81
789.91
789.39

599
Ac-LTF$r8AYWAQhF$S-NH2
1322
1579.84
790.92
791.14

600
Ac-LTF$r8AYWAQF3CF3$S-NH2
1323
1633.82
817.91
818.15

601
Ac-LTF$r8AYWAQF3Me$S-NH2
1324
1581.86
791.93
791.32

602
Ac-LTF$r8AYWAQ1Nal$S-NH2
1325
1615.84
808.92
809.18

603
Ac-LTF$r8AYWAQBip$S-NH2
1326
1641.86
821.93
822.13

604
Ac-LTF$r8FYWAQL$A-NH2
1327
1591.88
796.94
797.33

605
Ac-LTF$r8HYWAQL$S-NHAm
1328
1667.94
834.97
835.92

606
Ac-LTF$r8HYWAQL$S-NHiAm
1329
1667.94
834.97
835.55

607
Ac-LTF$r8HYWAQL$S-NHnPr3Ph
1330
1715.94
858.97
859.79

608
Ac-LTF$r8HYWAQL$S-NHnBu3,3Me
1331
1681.96
841.98
842.49

610
Ac-LTF$r8HYWAQL$S-NHnPr
1332
1639.91
820.96
821.58

611
Ac-LTF$r8HYWAQL$S-NHnEt2Ch
1333
1707.98
854.99
855.35

612
Ac-LTF$r8HYWAQL$S-NHHex
1334
1681.96
841.98
842.4

613
Ac-LTF$r8AYWAQL$S-NHmdPeg2
1335
1633.91
817.96
818.35

614
Ac-LTF$r8AYWAQL$A-NHmdPeg2
1336
1617.92
809.96
810.3

615
Ac-LTF$r8AYWAQL$A-NHmdPeg4
1337
1705.97
853.99
854.33

616
Ac-F$r8AYd14mWEAL$A-NH2
1338
1316.72
659.36
659.44

617
Ac-F$r8AYd15clWEAL$A-NH2
1339
1336.66
669.33
669.43

618
Ac-LThF$r8AYWAQL$S-NH2
1340
1545.86
773.93
774.11

619
Ac-LT2Nal$r8AYWAQL$S-NH2
1341
1581.86
791.93
792.43

620
Ac-LTA$r8AYWAQL$S-NH2
1342
1455.81
728.91
729.15

621
Ac-LTF$r8AYWVQL$S-NH2
1343
1559.88
780.94
781.24

622
Ac-LTF$r8HYWAAL$A-NH2
1344
1524.85
763.43
763.86

623
Ac-LTF$r8VYWAQL$A-NH2
1345
1543.88
772.94
773.37

624
Ac-LTF$r81YWAQL$S-NH2
1346
1573.89
787.95
788.17

625
Ac-FTF$r8VYWSQL$S-NH2
1347
1609.85
805.93
806.22

626
Ac-1TF$r8FYWAQL$S-NH2
1348
1607.88
804.94
805.2

627
Ac-2NalTF$r8VYWSQL$S-NH2
1349
1659.87
830.94
831.2

628
Ac-1TF$r8LYWSQL$S-NH2
1350
1589.89
795.95
796.13

629
Ac-FTF$r8FYWAQL$S-NH2
1351
1641.86
821.93
822.13

630
Ac-WTF$r8VYWAQL$S-NH2
1352
1632.87
817.44
817.69

631
Ac-WTF$r8WYVVAQL$S-NH2
1353
1719.88
860.94
861.36

632
Ac-VTF$r8AYWSQL$S-NH2
1354
1533.82
767.91
768.19

633
Ac-WTF$r8FYVVSQL$S-NH2
1355
1696.87
849.44
849.7

634
Ac-FTF$r81YWAQL$S-NH2
1356
1607.88
804.94
805.2

635
Ac-WTF$r8VYWSQL$S-NH2
1357
1648.87
825.44
824.8

636
Ac-FTF$r8LYWSQL$S-NH2
1358
1623.87
812.94
812.8

637
Ac-YTF$r8FYWSQL$S-NH2
1359
1673.85
837.93
837.8

638
Ac-LTF$r8AY6clWEAL$A-NH2
1360
1550.79
776.40
776.14

639
Ac-LTF$r8AY6clWSQL$S-NH2
1361
1581.80
791.90
791.68

640
Ac-F$r8AY6clWSAL$A-NH2
1362
1294.65
648.33
647.67

641
Ac-F$r8AY6clWQAL$AA-NH2
1363
1406.72
704.36
703.84

642
Ac-LHF$r8AYWAQL$S-NH2
1364
1567.86
784.93
785.21

643
Ac-LTF$r8AYWAQL$S-NH2
1365
1531.84
766.92
767.17

644
Ac-LTF$r8AHWAQL$S-NH2
1366
1505.84
753.92
754.13

645
Ac-LTF$r8AYWAHL$S-NH2
1367
1540.84
771.42
771.61

646
Ac-LTF$r8AYWAQL$H-NH2
1368
1581.87
791.94
792.15

647
H-LTF$r8AYWAQL$A-NH2
1369
1473.84
737.92
737.29

648
Ac-HHF$r8AYWAQL$S-NH2
1370
1591.83
796.92
797.35

649
Ac-aAibWTF$r8VYWSQL$S-NH2
1371
1804.96
903.48
903.64

650
Ac-AibWTF$r8HYWAQL$S-NH2
1372
1755.91
878.96
879.4

651
Ac-AibAWTF$r8HYWAQL$S-NH2
1373
1826.95
914.48
914.7

652
Ac-fWTF$r8HYWAQL$S-NH2
1374
1817.93
909.97
910.1

653
Ac-AibWWTF$r8HYWAQL$S-NH2
1375
1941.99
972.00
972.2

654
Ac-WTF$r8LYWSQL$S-NH2
1376
1662.88
832.44
832.8

655
Ac-WTF$r8NleYWSQL$S-NH2
1377
1662.88
832.44
832.6

656
Ac-LTF$r8AYWSQL$a-NH2
1378
1531.84
766.92
767.2

657
Ac-LTF$r8EYWARL$A-NH2
1379
1601.90
801.95
802.1

658
Ac-LTF$r8EYWAHL$A-NH2
1380
1582.86
792.43
792.6

659
Ac-aTF$r8AYWAQL$S-NH2
1381
1489.80
745.90
746.08

660
Ac-AibTF$r8AYWAQL$S-NH2
1382
1503.81
752.91
753.11

661
Ac-AmfTF$r8AYWAQLS-NH2
1383
1579.84
790.92
791.14

662
Ac-AmwTF$r8AYWAQL$S-NH2
1384
1618.86
810.43
810.66

663
Ac-NmLTF$r8AYWAQL$S-NH2
1385
1545.86
773.93
774.11

664
Ac-LNmTF$r8AYWAQL$S-NH2
1386
1545.86
773.93
774.11

665
Ac-LSarF$r8AYWAQL$S-NH2
1387
1501.83
751.92
752.18

667
Ac-LGF$r8AYWAQL$S-NH2
1388
1487.82
744.91
745.15

668
Ac-LTNmF$r8AYWAQL$S-NH2
1389
1545.86
773.93
774.2

669
Ac-TF$r8AYWAQLS-NH2
1390
1418.76
710.38
710.64

670
Ac-ETF$r8AYWAQL$A-NH2
1391
1531.81
766.91
767.2

671
Ac-LTF$r8EYWAQL$A-NH2
1392
1573.85
787.93
788.1

672
Ac-LT2Nal$r8AYWSQL$S-NH2
1393
1597.85
799.93
800.4

673
Ac-LTF$r8AYWAAL$S-NH2
1394
1474.82
738.41
738.68

674
Ac-LTF$r8AYWAQhCha$S-NH2
1395
1585.89
793.95
794.19

675
Ac-LTF$r8AYWAQChg$S-NH2
1396
1557.86
779.93
780.97

676
Ac-LTF$r8AYWAQCba$S-NH2
1397
1543.84
772.92
773.19

677
Ac-LTF$r8AYWAQF3CF3$S-NH2
1398
1633.82
817.91
818.15

678
Ac-LTF$r8AYWAQ1Nal$S-NH2
1399
1615.84
808.92
809.18

679
Ac-LTF$r8AYWAQBip$S-NH2
1400
1641.86
821.93
822.32

680
Ac-LT2Nal$r8AYWAQL$S-NH2
1401
1581.86
791.93
792.15

681
Ac-LTF$r8AYWVQL$S-NH2
1402
1559.88
780.94
781.62

682
Ac-LTF$r8AWWAQL$S-NH2
1403
1554.86
778.43
778.65

683
Ac-FTF$r8VYWSQL$S-NH2
1404
1609.85
805.93
806.12

684
Ac-1TF$r8FYWAQL$S-NH2
1405
1607.88
804.94
805.2

685
Ac-1TF$r8LYWSQL$S-NH2
1406
1589.89
795.95
796.22

686
Ac-FTF$r8FYWAQL$S-NH2
1407
1641.86
821.93
822.41

687
Ac-VTF$r8AYWSQL$S-NH2
1408
1533.82
767.91
768.19

688
Ac-LTF$r8AHWAQL$S-NH2
1409
1505.84
753.92
754.31

689
Ac-LTF$r8AYWAQL$H-NH2
1410
1581.87
791.94
791.94

690
Ac-LTF$r8AYWAHL$S-NH2
1411
1540.84
771.42
771.61

691
Ac-aAibWTF$r8VYWSQL$S-NH2
1412
1804.96
903.48
903.9

692
Ac-AibWTF$r8HYWAQL$S-NH2
1413
1755.91
878.96
879.5

693
Ac-AibAWTF$r8HYWAQL$S-NH2
1414
1826.95
914.48
914.7

694
Ac-fWTF$r8HYWAQL$S-NH2
1415
1817.93
909.97
910.2

695
Ac-AibWWTF$r8HYWAQL$S-NH2
1416
1941.99
972.00
972.7

696
Ac-WTF$r8LYWSQL$S-NH2
1417
1662.88
832.44
832.7

697
Ac-WTF$r8NleYWSQL$S-NH2
1418
1662.88
832.44
832.7

698
Ac-LTF$r8AYWSQL$a-NH2
1419
1531.84
766.92
767.2

699
Ac-LTF$r8EYWARL$A-NH2
1420
1601.90
801.95
802.2

700
Ac-LTF$r8EYWAHL$A-NH2
1421
1582.86
792.43
792.6

701
Ac-aTF$r8AYWAQL$S-NH2
1422
1489.80
745.90
746.1

702
Ac-AibTF$r8AYWAQL$S-NH2
1423
1503.81
752.91
753.2

703
Ac-AmfTF$r8AYWAQL$S-NH2
1424
1579.84
790.92
791.2

704
Ac-AmwTF$r8AYWAQL$S-NH2
1425
1618.86
810.43
810.7

705
Ac-NmLTF$r8AYWAQL$S-NH2
1426
1545.86
773.93
774.1

706
Ac-LNmTF$r8AYWAQL$S-NH2
1427
1545.86
773.93
774.4

707
Ac-LSarF$r8AYWAQL$S-NH2
1428
1501.83
751.92
752.1

708
Ac-TF$r8AYWAQL$S-NH2
1429
1418.76
710.38
710.8

709
Ac-ETF$r8AYWAQL$A-NH2
1430
1531.81
766.91
767.4

710
Ac-LTF$r8EYWAQL$A-NH2
1431
1573.85
787.93
788.2

711
Ac-WTF$r8VYWSQL$S-NH2
1432
1648.87
825.44
825.2

713
Ac-YTF$r8FYWSQL$S-NH2
1433
1673.85
837.93
837.3

714
Ac-F$r8AY6c1WSAL$A-NH2
1434
1294.65
648.33
647.74

715
Ac-ETF$r8EYWVQL$S-NH2
1435
1633.84
817.92
817.36

716
Ac-ETF$r8EHWAQL$A-NH2
1436
1563.81
782.91
782.36

717
Ac-ITF$r8EYWAQL$S-NH2
1437
1589.85
795.93
795.38

718
Ac-ITF$r8EHWVQL$A-NH2
1438
1575.88
788.94
788.42

719
Ac-ITF$r8EHWAQL$S-NH2
1439
1563.85
782.93
782.43

720
Ac-LTF4F$r8AYWAQCba$S-NH2
1440
1561.83
781.92
781.32

721
Ac-LTF3Cl$r8AYWAQhL$S-NH2
1441
1579.82
790.91
790.64

722
Ac-LTF3Cl$r8AYWAQCha$S-NH2
1442
1605.84
803.92
803.37

723
Ac-LTF3Cl$r8AYWAQChg$S-NH2
1443
1591.82
796.91
796.27

724
Ac-LTF3Cl$r8AYWAQCba$S-NH2
1444
1577.81
789.91
789.83

725
Ac-LTF$r8AY6clWSQL$S-NH2
1445
1581.80
791.90
791.75

726
Ac-LTF4F$r8HYWAQhL$S-NH2
1446
1629.87
815.94
815.36

727
Ac-LTF4F$r8HYWAQCba$S-NH2
1447
1627.86
814.93
814.32

728
Ac-LTF4F$r8AYWAQhL$S-NH2
1448
1563.85
782.93
782.36

729
Ac-LTF4F$r8AYWAQChg$S-NH2
1449
1575.85
788.93
788.35

730
Ac-ETF$r8EYWVAL$S-NH2
1450
1576.82
789.41
788.79

731
Ac-ETF$r8EHWAAL$A-NH2
1451
1506.79
754.40
754.8

732
Ac-1TF$r8EYWAAL$S-NH2
1452
1532.83
767.42
767.75

733
Ac-1TF$r8EHWVAL$A-NH2
1453
1518.86
760.43
760.81

734
Ac-1TF$r8EHWAAL$S-NH2
1454
1506.82
754.41
754.8

735
Pam-LTF$r8EYWAQL$S-NH2
1455
1786.07
894.04
894.48

736
Pam-ETF$r8EYWAQL$S-NH2
1456
1802.03
902.02
902.34

737
Ac-LTF$r8AYWLQL$S-NH2
1457
1573.89
787.95
787.39

738
Ac-LTF$r8EYWLQL$S-NH2
1458
1631.90
816.95
817.33

739
Ac-LTF$r8EHWLQL$S-NH2
1459
1605.89
803.95
804.29

740
Ac-LTF$r8VYWAQL$S-NH2
1460
1559.88
780.94
781.34

741
Ac-LTF$r8AYWSQL$S-NH2
1461
1547.84
774.92
775.33

742
Ac-ETF$r8AYWAQL$S-NH2
1462
1547.80
774.90
775.7

743
Ac-LTF$r8EYWAQL$S-NH2
1463
1589.85
795.93
796.33

744
Ac-LTF$r8HYWAQL$S-NHAm
1464
1667.94
834.97
835.37

745
Ac-LTF$r8HYWAQL$S-NHiAm
1465
1667.94
834.97
835.27

746
Ac-LTF$r8HYWAQL$S-NHnPr3Ph
1466
1715.94
858.97
859.42

747
Ac-LTF$r8HYWAQL$S-NHnBu3,3Me
1467
1681.96
841.98
842.67

748
Ac-LTF$r8HYWAQL$S-NHnBu
1468
1653.93
827.97
828.24

749
Ac-LTF$r8HYWAQL$S-NHnPr
1469
1639.91
820.96
821.31

750
Ac-LTF$r8HYWAQL$S-NHnEt2Ch
1470
1707.98
854.99
855.35

751
Ac-LTF$r8HYWAQL$S-NHHex
1471
1681.96
841.98
842.4

752
Ac-LTF$r8AYWAQL$S-NHmdPeg2
1472
1633.91
817.96
855.35

753
Ac-LTF$r8AYWAQL$A-NHmdPeg2
1473
1617.92
809.96
810.58

754
Ac-LTF$r5AYWAAL$s8S-NH2
1474
1474.82
738.41
738.79

755
Ac-LTF$r8AYWCouQL$S-NH2
1475
1705.88
853.94
854.61

756
Ac-LTF$r8CouYWAQL$S-NH2
1476
1705.88
853.94
854.7

757
Ac-CouTF$r8AYWAQL$S-NH2
1477
1663.83
832.92
833.33

758
H-LTF$r8AYWAQL$A-NH2
1478
1473.84
737.92
737.29

759
Ac-HHF$r8AYWAQL$S-NH2
1479
1591.83
796.92
797.72

760
Ac-LT2Nal$r8AYWSQL$S-NH2
1480
1597.85
799.93
800.68

761
Ac-LTF$r8HCouWAQL$S-NH2
1481
1679.87
840.94
841.38

762
Ac-LTF$r8AYWCou2QL$S-NH2
1482
1789.94
895.97
896.51

763
Ac-LTF$r8Cou2YWAQL$S-NH2
1483
1789.94
895.97
896.5

764
Ac-Cou2TF$r8AYWAQL$S-NH2
1484
1747.90
874.95
875.42

765
Ac-LTF$r8ACou2WAQL$S-NH2
1485
1697.92
849.96
850.82

766
Dmaac-LTF$r8AYWAQL$S-NH2
1486
1574.89
788.45
788.82

767
Hexac-LTF$r8AYWAQL$S-NH2
1487
1587.91
794.96
795.11

768
Napac-LTF$r8AYWAQL$S-NH2
1488
1657.89
829.95
830.36

769
Pam-LTF$r8AYWAQL$S-NH2
1489
1728.06
865.03
865.45

770
Ac-LT2Nal$r8HYAAQL$S-NH2
1490
1532.84
767.42
767.61

771
Ac-LT2Nal$/r8HYWAQL$/S-NH2
1491
1675.91
838.96
839.1

772
Ac-LT2Nal$r8HYFAQL$S-NH2
1492
1608.87
805.44
805.9

773
Ac-LT2Nal$r8HWAAQL$S-NH2
1493
1555.86
778.93
779.08

774
Ac-LT2Nal$r8HYAWQL$S-NH2
1494
1647.88
824.94
825.04

775
Ac-LT2Nal$r8HYAAQW$S-NH2
1495
1605.83
803.92
804.05

776
Ac-LTW$r8HYWAQL$S-NH2
1496
1636.88
819.44
819.95

777
Ac-LT1Nal$r8HYWAQL$S-NH2
1497
1647.88
824.94
825.41

778
Ac-F$r8ApmpEt6c1WEAL$A-NH2
1502
1470.71
736.36
788.17

In some embodiments, apeptidomimetic macrocycles disclosed herein do not comprise a peptidomimetic macrocycle structure as shown in Table 2b.

Table 2c shows examples of non-crosslinked polypeptides comprising D-amino acids.

SEQ

ID
Iso-
Exact
Found
Calc
Calc
Calc

SP
Sequence
NO:
mer
Mass
Mass
(M + 1)/1
(M + 2)/2
(M + 3)/3

SP765
Ac-tawyanfekllr-NH2
1498

777.46

SP766
Ac-tawyanf4CF3ekllr-NH2
1499

811.41

Example 3: X-Ray Co-Crystallography of Peptidomimetic Macrocycles in Complex with MDMX

For co-crystallization with peptide 46 (Table 2b), a stoichiometric amount of compound from a 100 mM stock solution in DMSO was added to the zebrafish MDMX protein solution and allowed to sit overnight at 4° C. before setting up crystallization experiments. Procedures were similar to those described by Popowicz et al. with some variations, as noted below. Protein (residues 15-129, L46V/V95L) was obtained from an E. coli BL21(DE3) expression system using the pET15b vector. Cells were grown at 37° C. and induced with 1 mM IPTG at an OD₆₀₀of 0.7. Cells were allowed to grow an additional 18 hr at 23° C. Protein was purified using Ni-NT Agarose followed by Superdex 75 buffered with 50 mM NaPO₄, pH 8.0, 150 mM NaCl, 2 mM TCEP and then concentrated to 24 mg/ml. The buffer was exchanged to 20 mM Tris, pH 8.0, 50 mM NaCl, 2 mM DTT for crystallization experiments. Initial crystals were obtained with the Nextal (Qiagen) AMS screen #94 and the final optimized reservoir was 2.6 M AMS, 75 mM Hepes, pH 7.5. Crystals grew routinely as thin plates at 4° C. and were cryo-protected by pulling them through a solution containing concentrated (3.4 M) malonate followed by flash cooling, storage, and shipment in liquid nitrogen.

Data collection was performed at the APS at beamline 31-ID (SGX-CAT) at 100° K. and wavelength 0.97929 Å. The beamline was equipped with a Rayonix 225-HE detector. For data collection, crystals were rotated through 180° in 1° increments using 0.8 second exposure times. Data were processed and reduced using Mosflm/scala (CCP4; see The CCP4 Suite: Programs for Protein Crystallography. Acta Crystallogr. D50, 760-763 (1994); P. R. Evans. Joint CCP4 and ESF-EACBM Newsletter 33, 22-24 (1997)) in space group C2 (unit cell: a=109.2786, b=81.0836, c=30.9058 Å, α=90, β=89.8577, γ=900). Molecular replacement with program Molrep (CCP4; seeA.Vagin & A. Teplyakov. J. Appl. Cryst. 30, 1022-1025 (1997)) was perfomed with the MDMX component of the structure determined by Popowicz et al. (2Z5S; see G. M. Popowicz, A. Czarna, U. Rothweiler, A. Szwagierczak, M. Krajewski, L. Weber & T. A. Holak. Cell Cycle 6, 2386-2392 (2007)) and identified two molecules in the asymmetric unit. Initial refinement of just the two molecules of the zebrafish MDMX with program Refmac (CCP4; see G. N. Murshudov, A. A. Vagin & E. J. Dodson. Acta Crystallogr. D53, 240-255 (1997)) resulted in an R-factor of 0.3424 (R_free=0.3712) and rmsd values for bonds (0.018 Å) and angles (1.698°). The electron density for the stapled peptide components, starting with Gln¹⁹and including all of the aliphatic staple, was very clear. Further refinement with CNX (Accelrys) using data to 2.3 Å resolution resulted in a model (comprised of 1448 atoms from MDMX, 272 atoms from the stapled peptides and 46 water molecules) that is well refined (R_f=0.2601, R_free=0.3162, rmsd bonds=0.007 Å and rmsd angles=0.916°).

Results from this Example are shown in FIGS. 1 and 2.

Example 4: Circular Dichroism (CD) Analysis of Alpha-Helicity

Peptide solutions were analyzed by CD spectroscopy using a Jasco J-815 spectropolarimeter (Jasco Inc., Easton, Md.) with the Jasco Spectra Manager Ver.2 system software. A Peltier temperature controller was used to maintain temperature control of the optical cell. Results are expressed as mean molar ellipticity [θ] (deg cm2 dmol-1) as calculated from the equation [θ]=θobs·MRW/10*l*c where θobs is the observed ellipticity in millidegrees, MRW is the mean residue weight of the peptide (peptide molecular weight/number of residues), l is the optical path length of the cell in centimeters, and c is the peptide concentration in mg/ml. Peptide concentrations were determined by amino acid analysis. Stock solutions of peptides were prepared in benign CD buffer (20 mM phosphoric acid, pH 2). The stocks were used to prepare peptide solutions of 0.05 mg/ml in either benign CD buffer or CD buffer with 50% trifluoroethanol (TFE) for analyses in a 10 mm pathlength cell. Variable wavelength measurements of peptide solutions were scanned at 4° C. from 195 to 250 nm, in 0.2 nm increments, and a scan rate 50 nm per minute. The average of six scans was reported.

Table 3 shows circular dichroism data for selected peptiomimetic macrocycles:

TABLE 3

Molar

Molar
Ellipticity
% Helix
% Helix

Molar
Ellipticity
TFE -
50% TFE
benign

Ellipticity
50% TFE
Molar
compared to
compared to

Benign (222
(222 in
Ellipticity
50% TFE
50% TFE

SP#
in 0% TFE)
50% TFE)
Benign
parent (CD)
parent (CD)

7
124
−19921.4
−20045.4
137.3
−0.9

11
−398.2
−16623.4
16225.2
106.1
2.5

41
−909
−21319.4
20410.4
136
5.8

43
−15334.5
−18247.4
2912.9
116.4
97.8

69
−102.6
−21509.7
−21407.1
148.2
0.7

71
−121.2
−17957
−17835.9
123.7
0.8

154
−916.2
−30965.1
−30048.9
213.4
6.3

230
−213.2
−17974
−17760.8
123.9
1.5

233
−477.9
−19032.6
−18554.7
131.2
3.3

Example 5: Direct Binding Assay MDM2 with Fluorescence Polarization (FP)

The assay was performed according to the following general protocol:

- 1. Dilute MDM2 (In-house, 41 kD) into FP buffer (High salt buffer-200 mM Nacl, 5 mM CHAPS, pH 7.5) to make 10μM working stock solution.
- 2. Add 30μl of 10 μM of protein stock solution into A1 and B1 well of 96-well black HE microplate (Molecular Devices).
- 3. Fill in 30μl of FP buffer into column A2 to A12, B2 to B12, C1 to C12, and D1 to D12.
- 4. 2 or 3 fold series dilution of protein stock from A1, B1 into A2, B2; A2, B2 to A3, B3; . . . to reach the single digit nM concentration at the last dilution point.
- 5. Dilute 1 mM (in 100% DMSO) of FAM labeled linear peptide with DMSO to 100μM (dilution 1:10). Then, dilute from 100μM to 10μM with water (dilution 1:10) and then dilute with FP buffer from 10μM to 40 nM (dilution 1:250). This is the working solution which will be a 10 nM concentration in well (dilution 1:4). Keep the diluted FAM labeled peptide in the dark until use.
- 6. Add 10μl of 10 nM of FAM labeled peptide into each well and incubate, and read at different time points. Kd with 5-FAM-BaLTFEHYWAQLTS-NH₂(SEQ ID NO: 943) is ˜13.38 nM.

Example 6: Competitive Fluorescence Polarization Assay for MDM2

The assay was performed according to the following general protocol:

- 1. Dilute MDM2 (In-house, 41 kD) into FP buffer (High salt buffer-200 mM Nacl, 5 mM CHAPS, pH 7.5) to make 84 nM (2×) working stock solution.
- 2. Add 20μl of 84 nM (2×) of protein stock solution into each well of 96-well black HE microplate (Molecular Devices)
- 3. Dilute 1 mM (in 100% DMSO) of FAM labeled linear peptide with DMSO to 100μM (dilution 1:10). Then, dilute from 100μM to 10μM with water (dilution 1:10) and then dilute with FP buffer from 10μM to 40 nM (dilution 1:250). This is the working solution which will be a 10 nM concentration in well (dilution 1:4). Keep the diluted FAM labeled peptide in the dark until use.
- 4. Make unlabeled peptide dose plate with FP buffer starting with 1μM (final) of peptide and making 5 fold serial dilutions for 6 points using following dilution scheme.
- Dilute 10 mM (in 100% DMSO) with DMSO to 5 mM (dilution 1:2). Then, dilute from 5 mM to 500μM with H₂O (dilution 1:10) and then dilute with FP buffer from 500μM to 20μM (dilution 1:25). Making 5 fold serial dilutions from 4 μM (4×) for 6 points.
- 5. Transfer 10μl of serial diluted unlabeled peptides to each well which is filled with 20μl of 84 nM of protein.
- 6. Add 10μl of 10 nM (4×) of FAM labeled peptide into each well and incubate for 3 hr to read.

Example 7: Direct Binding Assay MDMX with Fluorescence Polarization (FP)

The assay was performed according to the following general protocol:

- 1. Dilute MDMX (In-house, 40 kD) into FP buffer (High salt buffer-200 mM Nacl, 5 mM CHAPS, pH 7.5) to make 10μM working stock solution.
- 2. Add 30μl of 10 μM of protein stock solution into A1 and B1 well of 96-well black HE microplate (Molecular Devices).
- 3. Fill in 30μl of FP buffer into column A2 to A12, B2 to B12, C1 to C12, and D1 to D12.
- 4. 2 or 3 fold series dilution of protein stock from A1, B1 into A2, B2; A2, B2 to A3, B3; . . . to reach the single digit nM concentration at the last dilution point.
- 5. Dilute 1 mM (in 100% DMSO) of FAM labeled linear peptide with DMSO to 100μM (dilution 1:10). Then, dilute from 100μM to 10μM with water (dilution 1:10) and then dilute with FP buffer from 10μM to 40 nM (dilution 1:250). This is the working solution which will be a 10 nM concentration in well (dilution 1:4). Keep the diluted FAM labeled peptide in the dark until use.
- 6. Add 10μl of 10 nM of FAM labeled peptide into each well and incubate, and read at different time points.
- Kd with 5-FAM-BaLTFEHYWAQLTS-NH₂(SEQ ID NO: 943) is ˜51 nM.

Example 8: Competitive Fluorescence Polarization Assay for MDMX

The assay was performed according to the following general protocol:

- 1. Dilute MDMX (In-house, 40 kD) into FP buffer (High salt buffer-200 mM Nacl, 5 mM CHAPS, pH 7.5.) to make 300 nM (2×) working stock solution.
- 2. Add 20μl of 3 nM (2×) of protein stock solution into each well of 96-well black HE microplate (Molecular Devices)
- 3. Dilute 1 mM (in 100% DMSO) of FAM labeled linear peptide with DMSO to 100μM (dilution 1:10). Then, dilute from 100μM to 10μM with water (dilution 1:10) and then dilute with FP buffer from 10μM to 40 nM (dilution 1:250). This is the working solution which will be a 11 nM concentration in well (dilution 1:4). Keep the diluted FAM labeled peptide in the dark until use.
- 4. Make unlabeled peptide dose plate with FP buffer starting with 5μM (final) of peptide and making 5 fold serial dilutions for 6 points using following dilution scheme.
- 5. Dilute 10 mM (in 100% DMSO) with DMSO to 5 mM (dilution 1:2). Then, dilute from 5 mM to 500μM with H₂O (dilution 1:10) and then dilute with FP buffer from 500μM to 20μM (dilution 1:25). Making 5 fold serial dilutions from 20μM (4×) for 6 points.
- 6. Transfer 10μl of serial diluted unlabeled peptides to each well which is filled with 20μl of 300 nM of protein.
- 7. Add 10 μl of 10 nM (4×) of FAM labeled peptide into each well and incubate for 3 hr to read. Results from Examples 5-8 are shown in Table 4. The following scale is used: “+” represents a value greater than 1000 nM, “++” represents a value greater than 100 and less than or equal to 1000 nM, “+++” represents a value greater than 10 nM and less than or equal to 100 nM, and “++++” represents a value of less than or equal to 10 nM.

TABLE 4

SP#
IC50 (MDM2)
IC50 (MDMX)
Ki (MDM2)
Ki (MDMX)

3
++
++
+++
+++

4
+++
++
++++
+++

5
+++
++
++++
+++

6
++
++
+++
+++

7
+++
+++
++++
+++

8
++
++
+++
+++

9
++
++
+++
+++

10
++
++
+++
+++

11
+++
++
++++
+++

12
+
+
+++
++

13
++
++
+++
++

14
+++
+++
++++
++++

15
+++
++
+++
+++

16
+++
+++
++++
+++

17
+++
+++
++++
+++

18
+++
+++
++++
++++

19
++
+++
+++
+++

20
++
++
+++
+++

21
++
+++
+++
+++

22
+++
+++
++++
+++

23
++
++
+++
+++

24
+++
++
++++
+++

26
+++
++
++++
+++

28
+++
+++
++++
+++

30
++
++
+++
+++

32
+++
++
++++
+++

38
+
++
++
+++

39
+
++
++
++

40
++
++
++
+++

41
++
+++
+++
+++

42
++
++
+++
++

43
+++
+++
++++
+++

45
+++
+++
++++
++++

46
+++
+++
++++
+++

47
++
++
+++
+++

48
++
++
+++
+++

49
++
++
+++
+++

50
+++
++
++++
+++

52
+++
+++
++++
++++

54
++
++
+++
+++

55
+
+
++
++

65
+++
++
++++
+++

68
++
++
+++
+++

69
+++
++
++++
+++

70
++
++
++++
+++

71
+++
++
++++
+++

75
+++
++
++++
+++

77
+++
++
++++
+++

80
+++
++
++++
+++

81
++
++
+++
+++

82
++
++
+++
+++

85
+++
++
++++
+++

99
++++
++
++++
+++

100
++
++
++++
+++

101
+++
++
++++
+++

102
++
++
++++
+++

103
++
++
++++
+++

104
+++
++
++++
+++

105
+++
++
++++
+++

106
++
++
+++
+++

107
++
++
+++
+++

108
+++
++
++++
+++

109
+++
++
++++
+++

110
++
++
++++
+++

111
++
++
++++
+++

112
++
++
+++
+++

113
++
++
+++
+++

114
+++
++
++++
+++

115
++++
++
++++
+++

116
+
+
++
++

118
++++
++
++++
+++

120
+++
++
++++
+++

121
++++
++
++++
+++

122
++++
++
++++
+++

123
++++
++
++++
+++

124
++++
++
++++
+++

125
++++
++
++++
+++

126
++++
++
++++
+++

127
++++
++
++++
+++

128
++++
++
++++
+++

129
++++
++
++++
+++

130
++++
++
++++
+++

133
++++
++
++++
+++

134
++++
++
++++
+++

135
++++
++
++++
+++

136
++++
++
++++
+++

137
++++
++
++++
+++

139
++++
++
++++
+++

142
++++
+++
++++
+++

144
++++
++
++++
+++

146
++++
++
++++
+++

148
++++
++
++++
+++

150
++++
++
++++
+++

153
++++
+++
++++
+++

154
++++
+++
++++
++++

156
++++
++
++++
+++

158
++++
++
++++
+++

160
++++
++
++++
+++

161
++++
++
++++
+++

166
++++
++
++++
+++

167
+++
++
++++
++

169
++++
+++
++++
+++

170
++++
++
++++
+++

173
++++
++
++++
+++

175
++++
++
++++
+++

177
+++
++
++++
+++

180
+++
++
++++
+++

182
++++
++
++++
+++

185
+++
+
++++
++

186
+++
++
++++
+++

189
+++
++
++++
+++

192
+++
++
++++
+++

194
+++
++
++++
++

196
+++
++
++++
+++

197
++++
++
++++
+++

199
+++
++
++++
++

201
+++
++
++++
++

203
+++
++
++++
+++

204
+++
++
++++
+++

206
+++
++
++++
+++

207
++++
++
++++
+++

210
++++
++
++++
+++

211
++++
++
++++
+++

213
++++
++
++++
+++

215
+++
++
++++
+++

217
++++
++
++++
+++

218
++++
++
++++
+++

221
++++
+++
++++
+++

227
++++
++
++++
+++

230
++++
+++
++++
++++

232
++++
++
++++
+++

233
++++
+++
++++
+++

236
+++
++
++++
+++

237
+++
++
++++
+++

238
+++
+++
++++
+++

239
+++
++
+++
+++

240
+++
++
++++
+++

241
+++
++
++++
+++

242
+++
++
++++
+++

243
+++
+++
++++
+++

244
+++
+++
++++
++++

245
+++
+++
++++
+++

246
+++
++
++++
+++

247
+++
+++
++++
+++

248
+++
+++
++++
+++

249
+++
+++
++++
++++

250
++
+
++
+

252
++
+
++
+

254
+++
++
++++
+++

255
+++
+++
++++
+++

256
+++
+++
++++
+++

257
+++
+++
++++
+++

258
+++
++
++++
+++

259
+++
+++
++++
+++

260
+++
+++
++++
+++

261
+++
++
++++
+++

262
+++
++
++++
+++

263
+++
++
++++
+++

264
+++
+++
++++
+++

266
+++
++
++++
+++

267
+++
+++
++++
++++

270
++++
+++
++++
+++

271
++++
+++
++++
++++

272
++++
+++
++++
++++

276
+++
+++
++++
++++

277
+++
+++
++++
++++

278
+++
+++
++++
++++

279
++++
+++
++++
+++

280
+++
++
++++
+++

281
+++
+
+++
++

282
++
+
+++
+

283
+++
++
+++
++

284
+++
++
++++
+++

289
+++
+++
++++
+++

291
+++
+++
++++
++++

293
++++
+++
++++
+++

306
++++
++
++++
+++

308
++
++
+++
+++

310
+++
+++
++++
+++

312
+++
++
+++
+++

313
++++
++
++++
+++

314
++++
+++
++++
++++

315
+++
+++
++++
+++

316
++++
++
++++
+++

317
+++
++
+++
+++

318
+++
++
+++
+++

319
+++
++
+++
++

320
+++
++
+++
++

321
+++
++
++++
+++

322
+++
++
+++
++

323
+++
+
+++
++

328
+++
+++
++++
+++

329
+++
+++
++++
+++

331
++++
+++
++++
++++

332
++++
+++
++++
++++

334
++++
+++
++++
++++

336
++++
+++
++++
++++

339
++++
++
++++
+++

341
+++
+++
++++
++++

343
+++
+++
++++
++++

347
+++
+++
++++
+++

349
++++
+++
++++
++++

351
++++
+++
++++
++++

353
++++
+++
++++
++++

355
++++
+++
++++
++++

357
++++
+++
++++
++++

359
++++
+++
++++
+++

360
++++
++++
++++
++++

363
+++
+++
++++
++++

364
+++
+++
++++
++++

365
+++
+++
++++
++++

366
+++
+++
++++
+++

369
++
++
+++
+++

370
+++
+++
++++
+++

371
++
++
+++
+++

372
++
++
+++
+++

373
+++
+++
+++
+++

374
+++
+++
++++
++++

375
+++
+++
++++
++++

376
+++
+++
++++
++++

377
+++
+++
++++
+++

378
+++
+++
++++
+++

379
+++
+++
++++
+++

380
+++
+++
++++
+++

381
+++
+++
++++
+++

382
+++
+++
++++
++++

384
++
+
++
+

386
++
+
++
+

388
++
+++
+++
++++

390
+++
+++
++++
+++

392
+++
+++
++++
++++

394
++++
+++
++++
++++

396
++++
++++
++++
++++

398
+++
+++
++++
+++

402
++++
++++
++++
++++

404
+++
+++
++++
++++

408
+++
+++
++++
+++

410
++++
++++
++++
++++

411
++
+
++
+

412
++++
+++
++++
++++

415
++++
++++
++++
++++

416
+++
+++
++++
+++

417
+++
+++
++++
+++

418
++++
+++
++++
++++

419
+++
+++
+++
++++

421
++++
++++
++++
++++

423
+++
+++
++++
+++

425
+++
+++
+++
+++

427
++
++
+++
+++

432
++++
+++
++++
++++

434
+++
+++
++++
+++

435
++++
+++
++++
++++

437
+++
+++
++++
+++

439
++++
+++
++++
++++

441
++++
++++
++++
++++

443
+++
+++
++++
+++

445
+++
++
++++
+++

446
+++
+
++++
+

447
++
+
++
+

551
N/A
N/A
++++
+++

555
N/A
N/A
++++
+++

556
N/A
N/A
++++
+++

557
N/A
N/A
+++
+++

558
N/A
N/A
+++
+++

559
N/A
N/A
+++
+++

560
N/A
N/A
+
+

561
N/A
N/A
++++
+++

562
N/A
N/A
+++
+++

563
N/A
N/A
+++
+++

564
N/A
N/A
++++
+++

565
N/A
N/A
+++
+++

566
N/A
N/A
++++
+++

567
N/A
N/A
++++
+++

568
N/A
N/A
++++
++++

569
N/A
N/A
++++
+++

570
N/A
N/A
++++
+++

571
N/A
N/A
++++
+++

572
N/A
N/A
+++
+++

573
N/A
N/A
+++
+++

574
N/A
N/A
++++
+++

575
N/A
N/A
++++
+++

576
N/A
N/A
++++
+++

577
N/A
N/A
++++
+++

578
N/A
N/A
++++
+++

585
N/A
N/A
+++
+++

586
N/A
N/A
++++
+++

587
N/A
N/A
++++
++++

589
N/A
N/A
++++

594
N/A
N/A
++++
++++

596
N/A
N/A
++++
+++

597
N/A
N/A
++++
+++

598
N/A
N/A
++++
+++

600
N/A
N/A
++++
++++

602
N/A
N/A
++++
++++

603
N/A
N/A
++++
++++

604
N/A
N/A
+++
+++

608
N/A
N/A
++++
+++

609
N/A
N/A
++++
+++

610
N/A
N/A
++++
+++

611
N/A
N/A
++++
+++

612
N/A
N/A
++++
+++

613
N/A
N/A
++++
+++

615
N/A
N/A
++++
++++

433
N/A
N/A
++++
+++

686
N/A
N/A
++++
+++

687
N/A
N/A
++
++

595
N/A
N/A
+
N/A

665
N/A
N/A
+++
N/A

708
N/A
N/A
+++
+++

710
N/A
N/A
+++
+++

711
N/A
N/A
+++
++

712
N/A
N/A
++++
++++

713
N/A
N/A
++++
++++

716
N/A
N/A
++++
++++

765
+
+

766
+++
+

752
++
+

753
+++
+

754
++
+

755
++++
+

756
+++
+

757
++++
+

758
+++
+

Example 9: Competition Binding ELISA (MDM2 & MDMX)

p53-His6 protein (“His6” disclosed as SEQ ID NO: 1501) (30 nM/well) is coated overnight at room temperature in the wells of a 96-well Immulon plates. On the day of the experiment, plates are washed with 1× PBS-Tween 20 (0.05%) using an automated ELISA plate washer, blocked with ELISA Micro well Blocking for 30 minutes at room temperature; excess blocking agent is washed off by washing plates with 1× PBS-Tween 20 (0.05%). Peptides are diluted from 10 mM DMSO stocks to 500 μM working stocks in sterile water, further dilutions made in 0.5% DMSO to keep the concentration of DMSO constant across the samples. The peptides are added to wells at 2× desired concentrations in 50 μl volumes, followed by addition of diluted GST-MDM2 or GST-HMDX protein (final concentration: 10 nM). Samples are incubated at room temperature for 2 h, plates are washed with PBS-Tween 20 (0.05%) prior to adding 100 μl of HRP-conjugated anti-GST antibody [Hypromatrix, INC] diluted to 0.5 μg/ml in HRP-stabilizing buffer. Post 30 min incubation with detection antibody, plates are washed and incubated with 100 μl per well of TMB-E Substrate solution up to 30 minutes; reactions are stopped using 1M HCL and absorbance measured at 450 nm on micro plate reader. Data is analyzed using Graph Pad PRISM software.

Example 10: Cell Viability Assay

The assay was performed according to the following general protocol:

- Cell Plating: Trypsinize, count and seed cells at the pre-determined densities in 96-well plates a day prior to assay. Following cell densities are used for each cell line in use:

SJSA-1: 7500 cells/well

RKO: 5000 cells/well

RKO-E6: 5000 cells/well

HCT-116: 5000 cells/well

SW-480: 2000 cells/well

MCF-7: 5000 cells/well

On the day of study, replace media with fresh media with 11% FBS (assay media) at room temperature. Add 180 μL of the assay media per well. Control wells with no cells, receive 200 μl media.

Peptide dilution: all dilutions are made at room temperature and added to cells at room temperature.

- Prepare 10 mM stocks of the peptides in DMSO. Serially dilute the stock using 1:3 dilution scheme to get 10, 3.3, 1.1, 0.33, 0.11, 0.03, 0.01 mM solutions using DMSO as diluents. Dilute the serially DMSO-diluted peptides 33.3 times using sterile water. This gives range of 10× working stocks. Also prepare DMSO/sterile water (3% DMSO) mix for control wells.
- Thus the working stocks concentration range μM will be 300, 100, 30, 10, 3, 1, 0.3 and 0 μM. Mix well at each dilution step using multichannel.
- Row H has controls. H1-H3 will receive 20 μl of assay media. H4-H9 will receive 20 μL of 3% DMSO-water vehicle. H10-H12 will have media alone control with no cells.
- Positive control: MDM2 small molecule inhibitor, Nutlin-3a (10 mM) is used as positive control. Nutlin was diluted using the same dilution scheme as peptides.

Addition of working stocks to cells:

- Add 20 μl of 10× desired concentration to appropriate well to achieve the final concentrations in total 200 μl volume in well. (20 μl of 300 μM peptide+180 μl of cells in media=30 μM final concentration in 200 μl volume in wells). Mix gently a few times using pipette. Thus final concentration range used will be 30, 10, 3, 1, 0.3, 0.1, 0.03 & 0 μM (for potent peptides further dilutions are included).
- Controls include wells that get no peptides but contain the same concentration of DMSO as the wells containing the peptides, and wells containing NO CELLS.
- Incubate for 72 hours at 37° C. in humidified 5% CO₂atmosphere.
- The viability of cells is determined using MTT reagent from Promega. Viability of SJSA-1, RKO, RKO-E6, HCT-116 cells is determined on day 3, MCF-7 cells on day 5 and SW-480 cells on day 6. At the end of designated incubation time, allow the plates to come to room temperature. Remove 80 μl of assay media from each well. Add 15 μl of thawed MTT reagent to each well.
- Allow plate to incubate for 2 h at 37° C. in humidified 5% CO₂atmosphere and add 100 μl solubilization reagent as per manufacturer's protocol. Incubate with agitation for 1 h at room temperature and read on Synergy Biotek multiplate reader for absorbance at 570 nM.
- Analyze the cell viability against the DMSO controls using GraphPad PRISM analysis tools.

Reagents:

- Invitrogen cell culture Media
  - i. Falcon 96-well clear cell culture treated plates (Nunc 353072)
- DMSO (Sigma D 2650)
- RPMI 1640 (Invitrogen 72400)
- MIT (Promega G4000)

Instruments: Multiplate Reader for Absorbance readout (Synergy 2).

Results from cell viability assays are shown in Tables 5 and 6. The following scale is used: “+” represents a value greater than 30 μM, “++” represents a value greater than 15 μM and less than or equal to 30 μM, “+++” represents a value greater than 5 μM and less than or equal to 15 μM, and “++++” represents a value of less than or equal to 5 μM. “IC50 ratio” represents the ratio of average IC50 in p53+/+ cells relative to average IC50 in p53−/− cells.

TABLE 5

SP#
SJSA-1 EC50 (72 h)

3
+++

4
+++

5
++++

6
++

7
++++

8
+++

9
+++

10
+++

11
++++

12
++

13
+++

14
+

15
++

16
+

17
+

18
+

19
++

20
+

21
+

22
+

24
+++

26
++++

28
+

29
+

30
+

32
++

38
+

39
+

40
+

41
+

42
+

43
++

45
+

46
+

47
+

48
+

49
+++

50
++++

52
+

54
+

55
+

65
++++

68
++++

69
++++

70
++++

71
++++

72
++++

74
++++

75
++++

77
++++

78
++

80
++++

81
+++

82
+++

83
+++

84
+

85
+++

99
++++

102
+++

103
+++

104
+++

105
+++

108
+++

109
+++

110
+++

111
++

114
++++

115
++++

118
++++

120
++++

121
++++

122
++++

123
++++

124
+++

125
++++

126
++++

127
++++

128
+++

129
++

130
++++

131
+++

132
++++

133
+++

134
+++

135
+++

136
++

137
+++

139
++++

142
+++

144
++++

147
++++

148
++++

149
++++

150
++++

152
+++

153
++++

154
++++

155
++

156
+++

157
+++

158
+++

160
++++

161
++++

162
+++

163
+++

166
++

167
+++

168
++

169
++++

170
++++

171
++

173
+++

174
++++

175
+++

176
+++

177
++++

179
+++

180
+++

181
+++

182
++++

183
++++

184
+++

185
+++

186
++

188
++

190
++++

192
+++

193
++

194
+

195
++++

196
++++

197
++++

198
++

199
+++

200
+++

201
++++

202
+++

203
++++

204
++++

205
++

206
++

207
+++

208
+++

209
++++

210
+++

211
++++

213
++++

214
++++

215
++++

216
++++

217
++++

218
++++

219
++++

220
+++

221
++++

222
+++

223
++++

224
++

225
+++

226
++

227
+++

228
++++

229
++++

230
++++

231
++++

232
++++

233
++++

234
++++

235
++++

236
++++

237
++++

238
++++

239
+++

240
++

241
+++

242
++++

243
++++

244
++++

245
++++

246
+++

247
++++

248
++++

249
++++

250
++

251
+

252
+

253
+

254
+++

255
+++

256
++

257
+++

258
+++

259
++

260
++

261
++

262
+++

263
++

264
++++

266
+++

267
++++

270
++

271
++

272
++

276
++

277
++

278
++

279
++++

280
+++

281
++

282
++

283
++

284
++++

289
++++

290
+++

291
++++

292
++++

293
++++

294
++++

295
+++

296
++++

297
+++

298
++++

300
++++

301
++++

302
++++

303
++++

304
++++

305
++++

306
++++

307
+++

308
++++

309
+++

310
++++

312
++++

313
++++

314
++++

315
++++

316
++++

317
++++

318
++++

319
++++

320
++++

321
++++

322
++++

323
++++

324
++++

326
++++

327
++++

328
++++

329
++++

330
++++

331
++++

332
++++

333
++

334
+++

335
++++

336
++++

337
++++

338
++++

339
++++

340
++++

341
++++

342
++++

343
++++

344
++++

345
++++

346
++++

347
++++

348
++++

349
++++

350
++++

351
++++

352
++++

353
++++

355
++++

357
++++

358
++++

359
++++

360
++++

361
+++

362
++++

363
++++

364
++++

365
+++

366
++++

367
++++

368
+

369
++++

370
++++

371
++++

372
+++

373
+++

374
++++

375
++++

376
++++

377
++++

378
++++

379
++++

380
++++

381
++++

382
++++

386
+++

388
++

390
++++

392
+++

394
+++

396
+++

398
+++

402
+++

404
+++

408
++++

410
+++

411
+++

412
+

421
+++

423
++++

425
++++

427
++++

434
+++

435
++++

436
++++

437
++++

438
++++

439
++++

440
++++

441
++++

442
++++

443
++++

444
+++

445
++++

449
++++

551
++++

552
++++

554
+

555
++++

557
++++

558
++++

560
+

561
++++

562
++++

563
++++

564
++++

566
++++

567
++++

568
+++

569
++++

571
++++

572
++++

573
++++

574
++++

575
++++

576
++++

577
++++

578
++++

585
++++

586
++++

587
++++

588
++++

589
+++

432
++++

672
+

673
++

682
+

686
+

687
+

662
++++

663
++++

553
+++

559
++++

579
++++

581
++++

582
++

582
++++

584
+++

675
++++

676
++++

677
+

679
++++

700
+++

704
+++

591
+

706
++

695
++

595
++++

596
++++

597
+++

598
+++

599
++++

600
++++

601
+++

602
+++

603
+++

604
+++

606
++++

607
++++

608
++++

610
++++

611
++++

612
++++

613
+++

614
+++

615
++++

618
++++

619
++++

707
++++

620
++++

621
++++

622
++++

623
++++

624
++++

625
++++

626
+++

631
++++

633
++++

634
++++

635
+++

636
+++

638
+

641
+++

665
++++

708
++++

709
+++

710
+

711
++++

712
++++

713
++++

714
+++

715
+++

716
++++

765
+

753
+

754
+

755
+

756
+

757
++++

758
+++

TABLE 6

HCT-116
RKO
RKO-E6
SW480

EC50
EC50
EC50
EC50
IC50

SP#
(72 h)
(72 h)
(72 h)
(6 days)
Ratio

4
++++
++++
+++
++++

5
++++
++++
+++
++++

7
++++
++++
+++
++++

10
++++
+++
+++
+++

11
++++
++++
++
+++

50
++++
++++
++
+++

65
+++
+++
+++
+++

69
++++
++++
+
++++

70
++++
++++
++
+++

71
++++
++++
+++
+++

81
+++
+++
+++
+++

99
++++
++++
+++
++++

109
++++
++++
++
+++

114

+++
+
+++

115

+++
+
+++
1-29

118
+++
++++
+
++++

120
++++
++++
+
++++

121
++++
++++
+
++++

122

+++
+
+++
1-29

125
+++
+++
+
+

126
+
+
+
+

148

++
+
+

150

++
+
+

153
+++

+

154
+++
+++
+
+
30-49

158
+
+
+
+

160
+++
+
+
+
1-29

161
+++
+
+
+

175
+
+
+
+

196
++++
++++
+++
++++

219
++++
+++
+
+
1-29

233
++++

237
++++

+
+

238
++++

+
+

243
++++

+
+

244
++++

+
+
≥50

245
++++

+
+

247
++++

+
+

249
++++
++++
+
+
≥50

255
++++

+

291

+

293
+++

+

303
+++

+

1-29

305

+

306
++++

+

310
++++

+

312
++++

313
++++

++

314

+

315
++++
++++
++
++++
≥50

316
++++
++++
+
+++
≥50

317
+++

+
++

321
++++

+

324
+++

+

325
+++

326
+++

+

327
+++

+

328
+++

++

329
++++

+

330

+

331
++++
++++
+
+
≥50

338
++++
++++
++
+++

341
+++
++
+
+

343
+++

+
+

346
++++

+
+

347
+++

+
+

349
++++
+++
+
+
30-49

350
++++

+
+

351
++++
+++
+
+
30-49

353
++
++
+
+

355
++++
++
+
+
1-29

357
++++
++++
+
+

358
++++
++
+
+

359
++++
++
+
+

367
++++

+
+
30-49

386
++++
++++
++++
++++

388
++
++
+
+++
1-29

390
++++
++++
+++
++++

435
+++
++
+

436
++++
++++
++

437
++++
++++
++
++++
30-49

440
++
++
+

442
++++
++++
++

444
++++
++++
+++

445
++++
+++
+
+
≥50

555

≥50

557

≥50

558

30-49

562

30-49

564

30-49

566

30-49

567

≥50

572

≥50

573

30-49

578

30-49

662

≥50

379

1-29

375

1-29

559

≥50

561

1-29

563

1-29

568

1-29

569

1-29

571

1-29

574

1-29

575

1-29

576

1-29

577

30-49

433

1-29

551

30-49

553

1-29

710

+

711

+

712

++

713

++

714

+++

715

+++

716

+

Example 11: P21 ELISA Assay

The assay was performed according to the following general protocol:

Cell Plating:

- Trypsinize, count and seed SJSA1 cells at the density of 7500 cells/100 μl/well in 96-well plates a day prior to assay.
- On the day of study, replace media with fresh RPMI-11% FBS (assay media). Add 90 μL of the assay media per well. Control wells with no cells, receive 100 μl media.

Peptide dilution:

- Prepare 10 mM stocks of the peptides in DMSO. Serially dilute the stock using 1:3 dilution scheme to get 10, 3.3, 1.1, 0.33, 0.11, 0.03, 0.01 mM solutions using DMSO as diluents. Dilute the serially DMSO-diluted peptides 33.3 times using sterile water This gives range of 10× working stocks. Also prepare DMSO/sterile water (3% DMSO) mix for control wells.
- Thus the working stocks concentration range μM will be 300, 100, 30, 10, 3, 1, 0.3 and 0 μM. Mix well at each dilution step using multichannel.
- Row H has controls. H1-H3 will receive 10 μl of assay media. H4-H9 will receive 10 μl of 3% DMSO-water vehicle. H10-H12 will have media alone control with no cells.
- Positive control: MDM2 small molecule inhibitor, Nutlin-3a (10 mM) is used as positive control. Nutlin was diluted using the same dilution scheme as peptides.

Addition of working stocks to cells:

- Add 10 μl of 10× desired concentration to appropriate well to achieve the final concentrations in total 100 μl volume in well. (10 μl of 300 μM peptide+90 μl of cells in media=30 μM final concentration in 100 μl volume in wells). Thus final concentration range used will be 30, 10, 3, 1, 0.3& 0 μM.
- Controls will include wells that get no peptides but contain the same concentration of DMSO as the wells containing the peptides, and wells containing NO CELLS.
- 20 h-post incubation, aspirate the media; wash cells with 1× PBS (without Ca⁺⁺/Mg⁺⁺) and lyse in 60 μl of 1× Cell lysis buffer (Cell Signaling technologies 10× buffer diluted to 1× and supplemented with protease inhibitors and Phosphatase inhibitors) on ice for 30 min.
- Centrifuge plates in at 5000 rpm speed in at 4° C. for 8 min; collect clear supernatants and freeze at −80° C. till further use.

Protein Estimation:

- Total protein content of the lysates is measured using BCA protein detection kit and BSA standards from Thermofisher. Typically about 6-7 μg protein is expected per well.
- Use 50 μl of the lysate per well to set up p21 ELISA.

Human Total p21 ELISA:

The ELISA assay protocol is followed as per the manufacturer's instructions. 50 μl lysate is used for each well, and each well is set up in triplicate.

Reagents:

- Cell-Based Assay (−)-Nutlin-3 (10 mM): Cayman Chemicals, catalog #600034
- OptiMEM, Invitrogen catalog #51985
- Cell Signaling Lysis Buffer (10×), Cell signaling technology, Catalog #9803
- Protease inhibitor Cocktail tablets (mini), Roche Chemicals, catalog #04693124001
- Phosphatase inhibitor Cocktail tablet, Roche Chemicals, catalog #04906837001
- Human total p21 ELISA kit, R&D Systems, DYC1047-5
- STOP Solution (1M HCL), Cell Signaling Technologies, Catalog #7002

Instruments: Micro centrifuge-Eppendorf 5415D and Multiplate Reader for Absorbance readout (Synergy 2).

Example 12: Caspase 3 Detection Assay

The assay was performed according to the following general protocol:

Cell Plating:

Trypsinize, count and seed SJSA1 cells at the density of 7500 cells/100 μl/well in 96-well plates a day prior to assay. On the day of study, replace media with fresh RPMI-11% FBS (assay media). Add 180 μL of the assay media per well. Control wells with no cells, receive 200 μl media.

Peptide dilution:

- Prepare 10 mM stocks of the peptides in DMSO. Serially dilute the stock using 1:3 dilution scheme to get 10, 3.3, 1.1, 0.33, 0.11, 0.03, 0.01 mM solutions using DMSO as diluents. Dilute the serially DMSO-diluted peptides 33.3 times using sterile water This gives range of 10× working stocks. Also prepare DMSO/sterile water (3% DMSO) mix for control wells.
- Thus the working stocks concentration range μM will be 300, 100, 30, 10, 3, 1, 0.3 and 0 μM. Mix well at each dilution step using multichannel. Add 20 μl of 10× working stocks to appropriate wells.
- Row H has controls. H1-H3 will receive 20 μl of assay media. H4-H9 will receive 20 μl of 3% DMSO-water vehicle. H10-H12 will have media alone control with no cells.
- Positive control: MDM2 small molecule inhibitor, Nutlin-3a (10 mM) is used as positive control. Nutlin was diluted using the same dilution scheme as peptides.

Addition of working stocks to cells:

- Add 10 μl of 10× desired concentration to appropriate well to achieve the final concentrations in total 100 μl volume in well. (10 μl of 300 μM peptide+90 μl of cells in media=30 μM final concentration in 100 μl volume in wells). Thus final concentration range used will be 30, 10, 3, 1, 0.3& 0 μM.
- Controls will include wells that get no peptides but contain the same concentration of DMSO as the wells containing the peptides, and wells containing NO CELLS.
- 48 h-post incubation, aspirate 80 μl media from each well; add 100 μl Caspase3/7Glo assay reagent (Promega Caspase 3/7 glo assay system, G8092) per well, incubate with gentle shaking for 1 h at room temperature.
- read on Synergy Biotek multiplate reader for luminescence.
- Data is analyzed as Caspase 3 activation over DMSO-treated cells.

Results from Examples 11 and 12 are shown in Table 7:

TABLE 7

caspase
caspase
caspase
caspase
caspase
p21
p21
p21
p21
p21

SP#
0.3 uM
1 uM
3 uM
10 uM
30 uM
0.3 uM
1 uM
3 uM
10 uM
30uM

4

9
37
35

317
3049
3257

7
0.93
1.4
5.08
21.7
23.96

18
368
1687
2306

8

1
19
25

34
972
2857

10
1

1
17
32

10
89
970
2250

11
1

5
23
33.5

140
350
2075.5
3154

26
1

1
3
14

50

8
29
29

44
646
1923
1818

65
1

6
28
34
−69
−24
122
843
1472

69
4.34
9.51
16.39
26.59
26.11
272
458.72
1281.39
2138.88
1447.22

70

1
9
26

−19
68
828
1871

71
0.95
1.02
3.68
14.72
23.52

95
101
1204
2075

72
1

1
4
10
−19
57
282
772
1045

77
1

2
19
23

80
1

2
13
20

81
1

1
6
21

0
0
417
1649

99
1

7
31
33
−19
117
370
996
1398

109

4
16
25

161
445
1221
1680

114
1

6
28
34
−21
11
116
742
910

115
1

10
26
32
−10
36
315
832
1020

118
1

2
18
27
−76
−62
−11
581
1270

120
2

11
20
30
−4
30
164
756
1349

121
1

5
19
30
9
33
81
626
1251

122
1

2
15
30
−39
−18
59
554
1289

123
1

1
6
14

125
1

3
9
29
50
104
196
353
1222

126
1

1
6
30
−47
−10
90
397
1443

127
1

1
4
13

130
1

2
6
17

139
1

2
9
18

142
1

2
15
20

144
1

4
10
16

148
1

11
23
31
−23
55
295
666
820

149
1

2
4
10
35
331
601
1164
1540

150
2

11
19
35
−37
24
294
895
906

153
2

10
15
20

154
2.68
4
13.93
19.86
30.14
414.04
837.45
1622.42
2149.51
2156.98

158
1

1.67
5
16.33
−1.5
95
209.5
654
1665.5

160
2

10
16
31
−43
46
373
814
1334

161
2

8
14
22
13
128
331
619
1078

170
1

1
16
20

175
1

5
12
21
−65
1
149
543
1107

177
1

1
8
20

183
1

1
4
8
−132
−119
−14
1002
818

196
1

4
33
26
−49
−1
214
1715
687

197
1

1
10
20

203
1

3
12
10
77
329
534
1805
380

204
1

4
10
10
3
337
928
1435
269

218
1

2
8
18

219
1

5
17
34
28
53
289
884
1435

221
1

3
6
12
127
339
923
1694
1701

223
1

1
5
18

230
1

2
3
11
245.5
392
882
1549
2086

233
6
8
17
22
23
2000
2489
3528
3689
2481

237
1

5
9
15
0
0
2
284
421

238
1

2
4
21
0
149
128
825
2066

242
1

4
5
18
0
0
35
577
595

243
1

2
5
23
0
0
0
456
615

244
1

2
7
17
0
178
190
708
1112

245
1

3
9
16
0
0
0
368
536

247
1

3
11
24
0
0
49
492
699

248

0
50
22
174
1919

249
2

5
11
23
0
0
100
907
1076

251

0
0
0
0
0

252

0
0
0
0
0

253

0
0
0
0
0

254
1
3
7
14
22
118
896
1774
3042
3035

286
1
4
11
20
22
481
1351
2882
3383
2479

287
1
1
3
11
23
97
398
986
2828
3410

315
11
14.5
25.5
32
34
2110
2209
2626
2965
2635

316
6.5
10.5
21
32
32.5
1319
1718
2848
2918
2540

317
3
4
9
26
35
551
624
776
1367
1076

331
4.5
8
11
14.5
30.5
1510
1649
2027
2319
2509

338
1
5
23
20
29
660.37
1625.38
3365.87
2897.62
2727

341
3
8
11
14
21
1325.62
1873
2039.75
2360.75
2574

343
1
1
2
5
29
262
281
450
570
1199

346

235.86
339.82
620.36
829.32
1695.78

347
2
3
5
8
29
374
622
659
905
1567

349
1
8
11
16
24
1039.5
1598.88
1983.75
2191.25
2576.38

351
3
9
13
15
24
1350.67
1710.67
2030.92
2190.67
2668.54

353
1
2
5
7
30
390
490
709
931
1483

355
1
4
11
13
30
191
688
1122
1223
1519

357
2
7
11
15
23
539
777
1080
1362
1177

358
1
2
3
6
24
252
321
434
609
1192

359
3
9
11
13
23
1163.29
1508.79
1780.29
2067.67
2479.29

416

33.74
39.82
56.57
86.78
1275.28

417

0
0
101.13
639.04
2016.58

419

58.28
97.36
221.65
1520.69
2187.94

432

54.86
68.86
105.11
440.28
1594.4

Example 13. Cell Lysis by Peptidomimetic Macrocycles

SJSA-1 cells were plated out one day in advance in clear flat-bottom plates (Costar, catalog number 353072) at 7500 cells/well with 100 ul/well of growth media, leaving row H columns 10-12 empty for media alone. On the day of the assay, media was exchanged with RPMI 1% FBS media, 90 uL of media per well.

10 mM stock solutions of the peptidomimetic macrocycles were prepared in 100% DMSO. Peptidomimetic macrocycles were then diluted serially in 100% DMSO, and then further diluted 20-fold in sterile water to prepare working stock solutions in 5% DMSO/water of each peptidomimetic macrocycle at concentrations ranging from 500 μM to 62.5 μM.

10 μL of each compound was added to the 90 μL of SJSA-1 cells to yield final concentrations of 50 μM to 6.25 μM in 0.5% DMSO-containing media. The negative control (non-lytic) sample was 0.5% DMSO alone and positive control (lytic) samples include 10 μM Melittin and 1% Triton X-100.

Cell plates were incubated for 1 hour at 37 C. After the 1 hour incubation, the morphology of the cells is examined by microscope and then the plates were centrifuged at 1200 rpm for 5 minutes at room temperature. 40 uL of supernatant for each peptidomimetic macrocyle and control sample is transferred to clear assay plates. LDH release is measured using the LDH cytotoxicity assay kit from Caymen, catalog#1000882.

Results are shown in Table 8:

TABLE 8

6.25 uM %
12.5 uM %
25 uM %
50 uM %

Lysed cells
Lysed cells
Lysed cells
Lysed cells

SP#
(1 h LDH)
(1 h LDH)
(1 h LDH)
(1 h LDH)

3
1
0
1
3

4
−2
1
1
2

6
1
1
1
1

7
0
0
0
0

8
−1
0
1
1

9
−3
0
0
2

11
−2
1
2
3

15
1
2
2
5

18
0
1
2
4

19
2
2
3
21

22
0
−1
0
0

26
2
5
−1
0

32
0
0
2
0

39
0
−1
0
3

43
0
0
−1
−1

55
1
5
9
13

65
0
0
0
2

69
1
0.5
−0.5
5

71
0
0
0
0

72
2
1
0
3

75
−1
3
1
1

77
−2
−2
1
−1

80
0
1
1
5

81
1
1
0
0

82
0
0
0
1

99
1.5
3
2
3.5

108
0
0
0
1

114
3
−1
4
9

115
0
1
−1
6

118
4
2
2
4

120
0
−1
0
6

121
1
0
1
7

122
1
3
0
6

123
−2
2
5
3

125
0
1
0
2

126
1
2
1
1

130
1
3
0
−1

139
−2
−3
−1
−1

142
1
0
1
3

144
1
2
−1
2

147
8
9
16
55

148
0
1
−1
0

149
6
7
7
21

150
−1
−2
0
2

153
4
3
2
3

154
−1
−1.5
−1
−1

158
0
−6
−2

160
−1
0
−1
1

161
1
1
−1
0

169
2
3
3
7

170
2
2
1
−1

174
5
3
2
5

175
3
2
1
0

177
−1
−1
0
1

182
0
2
3
6

183
2
1
0
3

190
−1
−1
0
1

196
0
−2
0
3

197
1
−4
−1
−2

203
0
−1
2
2

204
4
3
2
0

211
5
4
3
1

217
2
1
1
2

218
0
−3
−4
1

219
0
0
−1
2

221
3
3
3
11

223
−2
−2
−4
−1

230
0.5
−0.5
0
3

232
6
6
5
5

233
2.5
4.5
3.5
6

237
0
3
7
55

243
4
23
39
64

244
0
1
0
4

245
1
14
11
56

247
0
0
0
4

249
0
0
0
0

254
11
34
60
75

279
6
4
5
6

280
5
4
6
18

284
5
4
5
6

286
0
0
0
0

287
0
6
11
56

316
0
1
0
1

317
0
1
0
0

331
0
0
0
0

335
0
0
0
1

336
0
0
0
0

338
0
0
0
1

340
0
2
0
0

341
0
0
0
0

343
0
1
0
0

347
0
0
0
0

349
0
0
0
0

351
0
0
0
0

353
0
0
0
0

355
0
0
0
0

357
0
0
0
0

359
0
0
0
0

413
5
3
3
3

414
3
3
2
2

415
4
4
2
2

Example 14: 53 GRIP Assay

Thermo Scientific* BioImage p53-MDM2 Redistribution Assay monitors the protein interaction with MDM2 and cellular translocation of GFP-tagged p53 in response to drug compounds or other stimuli. Recombinant CHO-hIR cells stably express human p53(1-312) fused to the C-terminus of enhanced green fluorescent protein (EGFP) and PDE4A4-MDM2(1-124), a fusion protein between PDE4A4 and MDM2(1-124). They provide a ready-to-use assay system for measuring the effects of experimental conditions on the interaction of p53 and MDM2. Imaging and analysis is performed with a HCS platform.

CHO-hIR cells are regularly maintained in Ham's F12 media supplemented with 1% Penicillin-Streptomycin, 0.5 mg/ml Geneticin, 1 mg/ml Zeocin and 10% FBS. Cells seeded into 96-well plates at the density of 7000 cells/100 μl per well 18-24 hours prior to running the assay using culture media. The next day, media is refreshed and PD177 is added to cells to the final concentration of 3 μM to activate foci formation. Control wells are kept without PD-177 solution. 24 h post stimulation with PD177, cells are washed once with Opti-MEM Media and 50 μL of the Opti-MEM Media supplemented with PD-177 (6 μM) is added to cells. Peptides are diluted from 10 mM DMSO stocks to 500 μM working stocks in sterile water, further dilutions made in 0.5% DMSO to keep the concentration of DMSO constant across the samples. Final highest DMSO concentration is 0.5% and is used as the negative control. Cayman Chemicals Cell-Based Assay (−)-Nutlin-3 (10 mM) is used as positive control. Nutlin was diluted using the same dilution scheme as peptides. 50 μl of 2× desired concentrations is added to the appropriate well to achieve the final desired concentrations. Cells are then incubated with peptides for 6 h at 37 C in humidified 5% CO2 atmosphere. Post-incubation period, cells are fixed by gently aspirating out the media and adding 150 μl of fixing solution per well for 20 minutes at room temperature. Fixed cells are washed 4 times with 200 μl PBS per well each time. At the end of last wash, 100 μl of 1 μM Hoechst staining solution is added. Sealed plates incubated for at least 30 min in dark, washed with PBS to remove excess stain and PBS is added to each well. Plates can be stored at 4° C. in dark up to 3 days. The translocation of p53/MDM2 is imaged using Molecular translocation module on Cellomics Arrayscan instrument using 10× objective, XF-100 filter sets for Hoechst and GFP. The output parameters was Mean-CircRINGAveIntenRatio (the ratio of average fluorescence intensities of nucleus and cytoplasm, (well average)). The minimally acceptable number of cells per well used for image analysis was set to 500 cells.

Example 15: MCF-7 Breast Cancer Study Using SP315, SP249 and SP154

A xenograft study was performed to test the efficacy of SP315, SP249 and SP154 in inhibiting tumor growth in athymic mice in the MCF-7 breast cancer xenograft model. A negative control stapled peptide. SP252, a point mutation of SP154 (F to A at position 19) was also tested in one group; this peptide had shown no activity in the SJSA-1 in vitro viability assay. Slow release 90 day 0.72 mg 17β-estradiol pellets (Innovative Research, Sarasota, Fla.) were implanted subcutaneously (sc) on the nape of the neck one day prior to tumor cell implantation (Day −1). On Day 0, MCF-7 tumor cells were implanted sc in the flank of female nude (Crl:NU-Foxn1nu) mice. On Day 18, the resultant sc tumors were measured using calipers to determine their length and width and the mice were weighed. The tumor sizes were calculated using the formula (length×width²)/2 and expressed as cubic millimeters (mm³). Mice with tumors smaller than 85.3 mm³or larger than 417.4 mm³were excluded from the subsequent group formation. Thirteen groups of mice, 10 mice per group, were formed by randomization such that the group mean tumor sizes were essentially equivalent (mean of groups±standard deviation of groups=180.7±17.5 mm³).

SP315, SP249, SP154 and SP252 dosing solutions were prepared from peptides formulated in a vehicle containing MPEG(2K)-DSPE at 50 mg/mL concentration in a 10 mM Histidine buffered saline at pH 7. This formulation was prepared once for the duration of the study. This vehicle was used as the vehicle control in the subsequent study.

Each group was assigned to a different treatment regimen. Group 1, as the vehicle negative control group, received the vehicle administered at 8 mL/kg body weight intravenously(iv) three times per week from Days 18-39. Groups 2 and 3 received SP154 as an iv injection at 30 mg/kg three times per week or 40 mg/kg twice a week, respectively. Group 4 received 6.7 mg/kg SP249 as an iv injection three times per week. Groups 5, 6, 7 and 8 received SP315 as an iv injection of 26.7 mg/kg three times per week, 20 mg/kg twice per week, 30 mg/kg twice per week, or 40 mg/kg twice per week, respectively. Group 9 received 30 mg/kg SP252 as an iv injection three times per week.

During the dosing period the mice were weighed and tumors measured 1-2 times per week. Results in terms of tumor volume are shown in FIGS. 3-6 and tumor growth inhibition compared with the vehicle group, body weight change and number of mice with ≥20% body weight loss or death are shown in Table 9. Tumor growth inhibition (TGI) was calculated as % TGI=100-[(TuVol^{Treated—day x}−TuVol^{Treated—day18})/(TuVol^{Vehicle negative control—day x}−TuVol^{Vehicle negative contorl—day}18)*100, where x=day that effect of treatment is being assessed. Group 1, the vehicle negative control group, showed good tumor growth rate for this tumor model.

For SP154, in the group dosed with 40 mg/kg twice a week 2 mice died during treatment, indicating that this dosing regimen was not tolerable. The dosing regimen of 30 mg/kg of SP154 three times per week was well-tolerated and yielded a TGI of 84%.

For SP249, the group dosed with 6.7 mg/kg three times per week 4 mice died during treatment, indicating that this dosing regimen was not tolerable.

All dosing regimens used for SP315 showed good tolerability, with no body weight loss or deaths noted. Dosing with 40 mg/kg of SP315 twice per week produced the highest TGI (92%). The dosing regimens of SP315 of 26.7 mg/kg three times per week, 20 mg/kg twice per week, 30 mg/kg twice per week produced TGI of 86, 82, and 85%, respectively.

For SP252, the point mutation of SP154 which shows no appreciable activity in in vitro assays, dosing with 30 mg/kg three times per week was well-tolerated with no body weight loss or deaths noted. While TGI of 88% was noted by Day 32, that TGI was reduced to 41% by Day 39.

Results from this Example are shown in FIGS. 3-6 and are summarized in Table 9.

TABLE 9

No.

No.
with ≥20%

Group
Treatment
% BW
with ≥10%
BW Loss

Number
Group
Change
BW Loss
or death
% TGI

1
Vehicle
+8.6
0/10
0/10
—

2
SP154
+5.7
0/10
0/10
*84

30 mg/kg

3x/wk iv

3
SP154
N/A
0/10
2/10
Regimen

40 mg/kg

(2 deaths)
not

2x/wk iv

tolerated

4
SP249
N/A
6/10
4/10
Regimen

6.7 mg/kg

not

3x/wk iv

tolerated

5
SP315
+3.7
0/10
0/10
*86

26.7 mg/kg

3x/wk iv

6
SP315
+3.9
0/10
0/10
*82

20 mg/kg

2x/wk iv

7
SP315
+8.0
0/10
0/10
*85

30 mg/kg

2x/wk iv

8
SP315
+2.1
0/10
0/10
*92

40 mg/kg

2x/wk iv

9
SP252
+3.3
0/10
0/10
*41

30 mg/kg

3x/wk iv

*p ≤ 0.05 Vs Vehicle Control

Example 21: Solubility Determination for Peptidomimetic Macrocycles

Peptidomimetic macrocyles are first dissolved in neat N,N-dimethylacetamide (DMA, Sigma-Aldrich, 38840-1L-F) to make 20× stock solutions over a concentration range of 20-140 mg/mL. The DMA stock solutions are diluted 20-fold in an aqueous vehicle containing 2% Solutol-HS-15, 25 mM Histidine, 45 mg/mL Mannitol to obtain final concentrations of 1-7 mg/ml of the peptidomimetic macrocycles in 5% DMA, 2% Solutol-HS-15, 25 mM Histidine, 45 mg/mL Mannitol. The final solutions are mixed gently by repeat pipetting or light vortexing, and then the final solutions are sonicated for 10 min at room temperature in an ultrasonic water bath. Careful visual observation is then performed under hood light using a 7× visual amplifier to determine if precipitate exists on the bottom or as a suspension. Additional concentration ranges are tested as needed to determine the maximum solubility limit for each peptidomimetic macrocycle.

Results from this Example are shown in FIG. 7.

Example 22: Preparation of Peptidomimetic Macrocycles Using a Boc-Protected Amino Acid

Peptidomimetic macrocycle precursors were prepared as described in Example 2 comprising an R8 amino acid at position “i” and an S5 amino acid at position “i+7”. The amino acid at position “i+3” was a Boc-protected tryptophan which was incorporated during solid-phase synthesis. Specifically, the Boc-protected tryptophan amino acid shown below (and commercially available, for example, from Novabiochem) was using during solid phase synthesis:

embedded image

Metathesis was performed using a ruthenium catalyst prior to the cleavage and deprotection steps. The composition obtained following cyclization was determined by HPLC analysis to contain primarily peptidomimetic macrocycles having a crosslinker comprising a trans olefin (“iso2”, comprising the double bond in an E configuration). Unexpectedly, a ratio of 90:10 was observed for the trans and cis products, respectively.

Claims

1. A method for treating a cancer, comprising administering to a subject with the cancer a therapeutically effective amount of a pharmaceutical product comprising: (a) a first therapeutic agent comprising an inhibitor of an interaction between p53 and MDM2 and/or an inhibitor of an interaction between p53 and MDMX, and(b) a second therapeutic agent comprising a chemotherapeutic agent;wherein the first therapeutic agent is a peptidomimetic macrocycle comprising an amino acid sequence with at least about 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ IP NOs: 10-457, or pharmaceutically acceptable salt thereof; and wherein the peptidomimetic macrocycle has a Formula:
2. The method of claim 1, wherein the first therapeutic agent and the second therapeutic agent are administered separately or as a single composition.
3. The method of claim 1, wherein the first therapeutic agent, the second therapeutic agent, or both are administered intravenously, intraperitoneally or subcutaneously.
4. The method of claim 1, wherein the second therapeutic agent is administered at a dosage of between 1% to 100% of a dosage of the second therapeutic agent normally administered in a monotherapy regimen.
5. The method of claim 1, wherein the cancer is selected from the group consisting of head and neck cancer, melanoma, lung cancer, breast cancer, and glioma.
6. The method of claim 1, wherein the cancer is a hematological cancer.
7. The method of claim 6, wherein the hematological cancer is acute myelogenous leukemia (AML).
8. The method of claim 1, wherein the second therapeutic agent is selected from the group consisting of a small molecule, a polypeptide, and an oligonucleotide.
9. The method of claim 1, wherein L and L′ are independently a macrocycle-forming linker of the formula -L1-L2-, wherein: L1 and L2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, or [-R4-K-R4-]n, each being optionally substituted with R5;each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, or heterocycloalkylene;each K is independently O, SO, SO2, CO, CO2, or CONR3; and each n is independently an integer from 1-5.
10. The method of claim 1, wherein L is alkylene, alkenylene, or alkynylene.
11. The method of claim 1, wherein R1 and R2 are independently -H or alkyl.
12. The method of claim 1, wherein v is an integer from 2-5.
13. The method of claim 1, wherein w is an integer from 3-6.
14. The method of claim 1, wherein [D]v is -Leu1-Thr2.
15. The method of claim 1, wherein each E is independently Ser or Ala.
16. The method of claim 5, wherein the cancer is head and neck cancer.
17. The method of claim 5, wherein the cancer is melanoma.
18. The method of claim 5, wherein the cancer is lung cancer.
19. The method of claim 5, wherein the cancer is breast cancer.
20. The method of claim 5, wherein the cancer is glioma.
21. The method of claim 6, wherein the hematological cancer is lymphoma.

CROSS-REFERENCE

This application is a continuation application of U.S. application Ser. No. 14/498,063, filed Sep. 26, 2014, which is a continuation application of U.S. application Ser. No. 13/767,852, filed Feb. 14, 2013, now U.S. Pat. No. 8,927,500, issued Jan. 6, 2015, which claims the benefit of U.S. Provisional Application No. 61/723,770, filed Nov. 7, 2012, U.S. Provisional Application No. 61/656,962, filed Jun. 7, 2012, and U.S. Provisional Application No. 61/599,328, filed Feb. 15, 2012; each of which is incorporated herein by reference in their entirety.

US Referenced Citations (596)

Number	Name	Date	Kind
4000259	Garsky	Dec 1976	A
4191754	Nutt et al.	Mar 1980	A
4270537	Romaine	Jun 1981	A
4438270	Bey et al.	Mar 1984	A
4518586	Rivier et al.	May 1985	A
4596556	Morrow et al.	Jun 1986	A
4683195	Mullis et al.	Jul 1987	A
4683202	Mullis	Jul 1987	A
4728726	Rivier et al.	Mar 1988	A
4730006	Bohme et al.	Mar 1988	A
4737465	Bond et al.	Apr 1988	A
4790824	Morrow et al.	Dec 1988	A
4880778	Bowers et al.	Nov 1989	A
4886499	Cirelli et al.	Dec 1989	A
4940460	Casey et al.	Jul 1990	A
4941880	Burns	Jul 1990	A
5015235	Crossman	May 1991	A
5036045	Thorner	Jul 1991	A
5043322	Rivier et al.	Aug 1991	A
5064413	McKinnon et al.	Nov 1991	A
5094951	Rosenberg	Mar 1992	A
5112808	Coy et al.	May 1992	A
5120859	Webb	Jun 1992	A
5141496	Dalto et al.	Aug 1992	A
5169932	Hoeger et al.	Dec 1992	A
5190521	Hubbard et al.	Mar 1993	A
5245009	Kornreich et al.	Sep 1993	A
5262519	Rivier et al.	Nov 1993	A
5296468	Hoeger et al.	Mar 1994	A
5310910	Drtina et al.	May 1994	A
5312335	McKinnon et al.	May 1994	A
5323907	Kalvelage	Jun 1994	A
5328483	Jacoby	Jul 1994	A
5334144	Alchas et al.	Aug 1994	A
5339163	Homma et al.	Aug 1994	A
5352796	Hoeger et al.	Oct 1994	A
5364851	Joran	Nov 1994	A
5371070	Koerber et al.	Dec 1994	A
5383851	McKinnon, Jr. et al.	Jan 1995	A
5384309	Barker et al.	Jan 1995	A
5416073	Coy et al.	May 1995	A
5417662	Hjertman et al.	May 1995	A
5446128	Kahn	Aug 1995	A
5453418	Anderson et al.	Sep 1995	A
5466220	Brenneman	Nov 1995	A
5480381	Weston	Jan 1996	A
5503627	McKinnon et al.	Apr 1996	A
5506207	Rivier et al.	Apr 1996	A
5520639	Peterson et al.	May 1996	A
5527288	Gross et al.	Jun 1996	A
5552520	Kim et al.	Sep 1996	A
5569189	Parsons	Oct 1996	A
5580957	Hoeger et al.	Dec 1996	A
5599302	Lilley et al.	Feb 1997	A
5620708	Amkraut et al.	Apr 1997	A
5622852	Korsmeyer	Apr 1997	A
5629020	Leone-Bay et al.	May 1997	A
5635371	Stout et al.	Jun 1997	A
5643957	Leone-Bay et al.	Jul 1997	A
5649912	Peterson	Jul 1997	A
5650133	Carvalho et al.	Jul 1997	A
5650386	Leone-Bay et al.	Jul 1997	A
5656721	Albert et al.	Aug 1997	A
5663316	Xudong	Sep 1997	A
5672584	Borchardt et al.	Sep 1997	A
5681928	Rivier et al.	Oct 1997	A
5700775	Gutniak et al.	Dec 1997	A
5702908	Picksley et al.	Dec 1997	A
5704911	Parsons	Jan 1998	A
5708136	Burrell et al.	Jan 1998	A
5710245	Kahn	Jan 1998	A
5710249	Hoeger et al.	Jan 1998	A
5731408	Hadley et al.	Mar 1998	A
5744450	Hoeger et al.	Apr 1998	A
5750499	Hoeger et al.	May 1998	A
5750767	Carpino et al.	May 1998	A
5756669	Bischoff et al.	May 1998	A
5770377	Picksley et al.	Jun 1998	A
5792747	Schally et al.	Aug 1998	A
5807983	Jiang et al.	Sep 1998	A
5811515	Grubbs et al.	Sep 1998	A
5817752	Yu	Oct 1998	A
5817789	Heartlein et al.	Oct 1998	A
5824483	Houston, Jr. et al.	Oct 1998	A
5834209	Korsmeyer	Nov 1998	A
5837845	Hosokawa et al.	Nov 1998	A
5840833	Kahn	Nov 1998	A
5846936	Felix et al.	Dec 1998	A
5847066	Coy et al.	Dec 1998	A
5854216	Gaudreau	Dec 1998	A
5856445	Korsmeyer	Jan 1999	A
5859184	Kahn et al.	Jan 1999	A
5861379	Ibea et al.	Jan 1999	A
5874529	Gilon et al.	Feb 1999	A
5893397	Peterson et al.	Apr 1999	A
5922863	Grubbs et al.	Jul 1999	A
5939386	Ibea et al.	Aug 1999	A
5939387	Broderick et al.	Aug 1999	A
5955593	Korsmeyer	Sep 1999	A
5965703	Horne et al.	Oct 1999	A
5993412	Deily et al.	Nov 1999	A
5998583	Korsmeyer	Dec 1999	A
6020311	Brazeau et al.	Feb 2000	A
6030997	Eilat et al.	Feb 2000	A
6031073	Yu	Feb 2000	A
6043339	Lin et al.	Mar 2000	A
6046289	Komazawa et al.	Apr 2000	A
6051513	Kumazawa et al.	Apr 2000	A
6051554	Hornik et al.	Apr 2000	A
6054556	Huby et al.	Apr 2000	A
6060513	Leone-Bay et al.	May 2000	A
6066470	Nishimura et al.	May 2000	A
6071510	Leone-Bay et al.	Jun 2000	A
6071538	Milstein et al.	Jun 2000	A
6071926	Van Cauter et al.	Jun 2000	A
6090958	Leone-Bay et al.	Jul 2000	A
6100298	Leone-Bay et al.	Aug 2000	A
6118010	Ueda et al.	Sep 2000	A
6123964	Asgharnejad et al.	Sep 2000	A
6127341	Hansen et al.	Oct 2000	A
6127354	Peschke et al.	Oct 2000	A
6127391	Hansen et al.	Oct 2000	A
6153391	Picksley et al.	Nov 2000	A
6169073	Halazonetis et al.	Jan 2001	B1
6177076	Lattime et al.	Jan 2001	B1
6177542	Ruoslahti et al.	Jan 2001	B1
6184344	Kent et al.	Feb 2001	B1
6190699	Luzzi et al.	Feb 2001	B1
6194384	Brazeau et al.	Feb 2001	B1
6194402	Bach et al.	Feb 2001	B1
6204361	Carpino et al.	Mar 2001	B1
6245359	Milstein et al.	Jun 2001	B1
6245886	Halazonetis et al.	Jun 2001	B1
6248358	Bologna et al.	Jun 2001	B1
6271198	Braisted et al.	Aug 2001	B1
6274584	Peschke et al.	Aug 2001	B1
6287787	Houghten et al.	Sep 2001	B1
6307017	Coy et al.	Oct 2001	B1
6309859	Nishimura et al.	Oct 2001	B1
6313088	Leone-Bay et al.	Nov 2001	B1
6313133	Van Cauter et al.	Nov 2001	B1
6326354	Gross et al.	Dec 2001	B1
6331318	Milstein	Dec 2001	B1
6344213	Leone-Bay et al.	Feb 2002	B1
6346264	White	Feb 2002	B1
6348558	Harris et al.	Feb 2002	B1
6368617	Hastings et al.	Apr 2002	B1
6420118	Halazonetis et al.	Jul 2002	B1
6420136	Riabowol et al.	Jul 2002	B1
6444425	Reed et al.	Sep 2002	B1
6458764	Gravel et al.	Oct 2002	B1
6461634	Marshall	Oct 2002	B1
6495589	Hay et al.	Dec 2002	B2
6495674	Lemke et al.	Dec 2002	B1
6514685	Moro	Feb 2003	B1
6548501	Hakkinen	Apr 2003	B2
6555156	Loughman	Apr 2003	B1
6555570	Hansen et al.	Apr 2003	B2
6569993	Sledeski et al.	May 2003	B1
6572856	Taylor et al.	Jun 2003	B1
6579967	Rivier et al.	Jun 2003	B1
6610657	Goueli	Aug 2003	B1
6613874	Mazur et al.	Sep 2003	B1
6617360	Bailey et al.	Sep 2003	B1
6620808	Van Der Klish et al.	Sep 2003	B2
6635740	Enright et al.	Oct 2003	B1
6641840	Am Ende et al.	Nov 2003	B2
6686148	Shen et al.	Feb 2004	B1
6696063	Torres	Feb 2004	B1
6696418	Hay et al.	Feb 2004	B1
6703382	Wang et al.	Mar 2004	B2
6713280	Huang et al.	Mar 2004	B1
6720330	Hay et al.	Apr 2004	B2
6747125	Hoeger et al.	Jun 2004	B1
6784157	Halazonetis et al.	Aug 2004	B2
6849428	Evans et al.	Feb 2005	B1
6852722	Hakkinen	Feb 2005	B2
6875594	Muir et al.	Apr 2005	B2
6897286	Jaspers et al.	May 2005	B2
6936586	Larsen et al.	Aug 2005	B1
6939880	Hansen et al.	Sep 2005	B2
7019109	Rivier et al.	Mar 2006	B2
7034050	Deghenghi	Apr 2006	B2
7064193	Cory et al.	Jun 2006	B1
7083983	Lane et al.	Aug 2006	B2
7084244	Gilon et al.	Aug 2006	B2
7115372	Shen et al.	Oct 2006	B2
7144577	Torres	Dec 2006	B2
7166461	Schwartz et al.	Jan 2007	B2
7183059	Verdine et al.	Feb 2007	B2
7189801	Halazonetis et al.	Mar 2007	B2
7192713	Verdine et al.	Mar 2007	B1
7202332	Arora et al.	Apr 2007	B2
7238775	Rivier et al.	Jul 2007	B2
7247700	Korsmeyer et al.	Jul 2007	B2
7268113	Bridon et al.	Sep 2007	B2
7312304	Coy et al.	Dec 2007	B2
7316997	Abribat et al.	Jan 2008	B2
7414107	Larsen et al.	Aug 2008	B2
7425542	Maggio	Sep 2008	B2
7445919	Jaspers et al.	Nov 2008	B2
7476653	Hoveyda et al.	Jan 2009	B2
7485620	Ghigo et al.	Feb 2009	B2
7491695	Fraser et al.	Feb 2009	B2
7521420	Fraser et al.	Apr 2009	B2
7538190	Robinson et al.	May 2009	B2
7566777	Enright et al.	Jul 2009	B2
7638138	Oki et al.	Dec 2009	B2
7655447	Jaspers et al.	Feb 2010	B2
7666983	Halazonetis et al.	Feb 2010	B2
7705118	Arora et al.	Apr 2010	B2
7723469	Walensky et al.	May 2010	B2
7737174	Wang et al.	Jun 2010	B2
7745573	Robinson et al.	Jun 2010	B2
7759383	Wang et al.	Jul 2010	B2
7786072	Verdine et al.	Aug 2010	B2
7829724	Perrissoud et al.	Nov 2010	B2
RE42013	Hoveyda	Dec 2010	E
7884073	Guyon et al.	Feb 2011	B2
7884107	Ma et al.	Feb 2011	B2
7888056	Sheppard et al.	Feb 2011	B2
7893025	Lussier et al.	Feb 2011	B2
7893278	Haley et al.	Feb 2011	B2
7927813	Geneste et al.	Apr 2011	B2
7932397	Hock et al.	Apr 2011	B2
7960342	Rivier et al.	Jun 2011	B2
7960506	Nash	Jun 2011	B2
7964724	Fotouhi et al.	Jun 2011	B2
7981998	Nash	Jul 2011	B2
7981999	Nash	Jul 2011	B2
RE42624	Fraser	Aug 2011	E
7994329	Andersen et al.	Aug 2011	B2
7998927	Maggio	Aug 2011	B2
7998930	Guyon et al.	Aug 2011	B2
8017607	Bartkovitz et al.	Sep 2011	B2
8039456	Polvino et al.	Oct 2011	B2
8039457	Polvino	Oct 2011	B2
8058269	Chen et al.	Nov 2011	B2
8071541	Arora et al.	Dec 2011	B2
8076290	Maggio	Dec 2011	B2
8076482	Chen et al.	Dec 2011	B2
8084022	Maggio	Dec 2011	B2
8088733	Fraser et al.	Jan 2012	B2
8088815	Bartkovitz et al.	Jan 2012	B2
8088931	Wang et al.	Jan 2012	B2
8124356	Sheppard et al.	Feb 2012	B2
8124726	Robinson et al.	Feb 2012	B2
8129561	Marsault et al.	Mar 2012	B2
8133863	Maggio	Mar 2012	B2
8173594	Maggio	May 2012	B2
8192719	Larsen	Jun 2012	B2
8198405	Walensky et al.	Jun 2012	B2
8217051	Zhang et al.	Jul 2012	B2
8222209	Guyon et al.	Jul 2012	B2
8226949	Maggio	Jul 2012	B2
8288377	Storck	Oct 2012	B2
8314066	Abribat et al.	Nov 2012	B2
8324428	Verdine et al.	Dec 2012	B2
8334256	Marsault et al.	Dec 2012	B2
8343760	Lu et al.	Jan 2013	B2
8349887	Fraser et al.	Jan 2013	B2
8389484	Shen et al.	Mar 2013	B2
8399405	Nash et al.	Mar 2013	B2
8435945	Abribat et al.	May 2013	B2
8450268	Fraser et al.	May 2013	B2
8524653	Nash et al.	Sep 2013	B2
8583380	Stephan et al.	Nov 2013	B2
8592377	Verdine et al.	Nov 2013	B2
8609809	Nash	Dec 2013	B2
8637686	Nash	Jan 2014	B2
8796418	Walensky et al.	Aug 2014	B2
8808694	Nash et al.	Aug 2014	B2
8859723	Guerlavais et al.	Oct 2014	B2
8871899	Wang et al.	Oct 2014	B2
8889632	Bernal et al.	Nov 2014	B2
8895699	Verdine et al.	Nov 2014	B2
8927500	Guerlavais et al.	Jan 2015	B2
8957026	Verdine et al.	Feb 2015	B2
8987414	Guerlavais et al.	Mar 2015	B2
9023988	Nash	May 2015	B2
9074009	Bradner et al.	Jul 2015	B2
9096684	Kawahata et al.	Aug 2015	B2
9163330	Verdine et al.	Oct 2015	B2
9175045	Nash et al.	Nov 2015	B2
9175047	Nash et al.	Nov 2015	B2
9175056	Nash	Nov 2015	B2
9206223	Nash et al.	Dec 2015	B2
9273099	Walensky et al.	Mar 2016	B2
9458189	Verdine et al.	Oct 2016	B2
9487562	Moellering et al.	Nov 2016	B2
9617309	Verdine et al.	Apr 2017	B2
9845287	Darlak et al.	Dec 2017	B2
9951099	Verdine et al.	Apr 2018	B2
9957296	Nash et al.	May 2018	B2
9957299	Guerlavais et al.	May 2018	B2
1002242	Nash et al.	Jul 2018	A1
1002361	Guerlavais et al.	Jul 2018	A1
20010047030	Hay et al.	Nov 2001	A1
20020002198	Parr	Jan 2002	A1
20020013320	Busch et al.	Jan 2002	A1
20020016298	Hay et al.	Feb 2002	A1
20020028838	MacLean et al.	Mar 2002	A1
20020055156	Jaspers et al.	May 2002	A1
20020061838	Holmquist et al.	May 2002	A1
20020091090	Cole et al.	Jul 2002	A1
20020091125	Hay et al.	Jul 2002	A1
20020094992	MacLean	Jul 2002	A1
20020098580	Nandabalan et al.	Jul 2002	A1
20020103221	Petrie et al.	Aug 2002	A1
20020128206	Hay et al.	Sep 2002	A1
20020132977	Yuan et al.	Sep 2002	A1
20020137665	Evans et al.	Sep 2002	A1
20020173618	Rivier et al.	Nov 2002	A1
20030027766	Ioannides et al.	Feb 2003	A1
20030060432	Tocque et al.	Mar 2003	A1
20030074679	Schwartz et al.	Apr 2003	A1
20030083241	Young	May 2003	A1
20030105114	Carpino et al.	Jun 2003	A1
20030144331	Gudkov et al.	Jul 2003	A1
20030148948	Schwartz et al.	Aug 2003	A1
20030157717	Draghia-Akli	Aug 2003	A1
20030166138	Kinsella et al.	Sep 2003	A1
20030176318	Gudkov et al.	Sep 2003	A1
20030181367	O'Mahony et al.	Sep 2003	A1
20030186865	Acosta et al.	Oct 2003	A1
20030204063	Gravel et al.	Oct 2003	A1
20040018967	Enright et al.	Jan 2004	A1
20040023887	Pillutla et al.	Feb 2004	A1
20040038901	Basler et al.	Feb 2004	A1
20040038918	Draghia-Akli et al.	Feb 2004	A1
20040058877	Hay et al.	Mar 2004	A1
20040067503	Tan et al.	Apr 2004	A1
20040081652	Zack et al.	Apr 2004	A1
20040091530	Am Ende et al.	May 2004	A1
20040106159	Kern et al.	Jun 2004	A1
20040106548	Schmidt et al.	Jun 2004	A1
20040115135	Quay	Jun 2004	A1
20040122062	MacLean et al.	Jun 2004	A1
20040146971	Lane et al.	Jul 2004	A1
20040152708	Li et al.	Aug 2004	A1
20040157834	Hay et al.	Aug 2004	A1
20040170653	Stanislawski et al.	Sep 2004	A1
20040170971	Kinzler et al.	Sep 2004	A1
20040171530	Coy et al.	Sep 2004	A1
20040171809	Korsmeyer et al.	Sep 2004	A1
20040195413	Reed et al.	Oct 2004	A1
20040204358	Brown et al.	Oct 2004	A1
20040208866	Jaspers et al.	Oct 2004	A1
20040228866	Lu	Nov 2004	A1
20040230380	Chirino et al.	Nov 2004	A1
20040235746	Hawiger et al.	Nov 2004	A1
20040248198	Kriwacki et al.	Dec 2004	A1
20040248788	Vickers et al.	Dec 2004	A1
20040265931	Gu et al.	Dec 2004	A1
20050009739	Wang et al.	Jan 2005	A1
20050013820	Holoshitz et al.	Jan 2005	A1
20050014686	Albert et al.	Jan 2005	A1
20050031549	Quay et al.	Feb 2005	A1
20050037383	Taremi et al.	Feb 2005	A1
20050043231	Cutfield et al.	Feb 2005	A1
20050048618	Jaspers et al.	Mar 2005	A1
20050049177	Bachovchin et al.	Mar 2005	A1
20050054581	Hay et al.	Mar 2005	A1
20050059605	Peri et al.	Mar 2005	A1
20050065180	Lee	Mar 2005	A1
20050080007	Ghigo et al.	Apr 2005	A1
20050089511	Roth et al.	Apr 2005	A1
20050119167	Abbenante et al.	Jun 2005	A1
20050137137	Lane et al.	Jun 2005	A1
20050147581	Zamiri et al.	Jul 2005	A1
20050164298	Golz et al.	Jul 2005	A1
20050176075	Jones et al.	Aug 2005	A1
20050203009	Pan et al.	Sep 2005	A1
20050222224	Gudkov et al.	Oct 2005	A1
20050222427	Sharpless et al.	Oct 2005	A1
20050227932	Lu et al.	Oct 2005	A1
20050245438	Rivier et al.	Nov 2005	A1
20050245457	Deghenghi	Nov 2005	A1
20050245764	Yamashita et al.	Nov 2005	A1
20050250680	Walensky et al.	Nov 2005	A1
20050261201	Polvino et al.	Nov 2005	A1
20050277764	Boyd et al.	Dec 2005	A1
20060008848	Verdine et al.	Jan 2006	A1
20060014675	Arora et al.	Jan 2006	A1
20060025344	Lange et al.	Feb 2006	A1
20060058219	Miller et al.	Mar 2006	A1
20060058221	Miller et al.	Mar 2006	A1
20060073518	Timmerman et al.	Apr 2006	A1
20060100143	Lu et al.	May 2006	A1
20060111411	Cooper et al.	May 2006	A1
20060128615	Gaudreau	Jun 2006	A1
20060142181	Miller et al.	Jun 2006	A1
20060142182	Miller et al.	Jun 2006	A1
20060148715	Tweardy	Jul 2006	A1
20060149039	Hunter et al.	Jul 2006	A1
20060155107	Rivier et al.	Jul 2006	A1
20060189511	Koblish et al.	Aug 2006	A1
20060210641	Shalaby	Sep 2006	A1
20060217296	Jansson	Sep 2006	A1
20060233779	Ben-Avraham et al.	Oct 2006	A1
20060247170	Guyon et al.	Nov 2006	A1
20060293380	Nantermet et al.	Dec 2006	A1
20070004765	Graffner-Nordberg et al.	Jan 2007	A1
20070006332	O'Neill	Jan 2007	A1
20070020620	Finn et al.	Jan 2007	A1
20070025991	Pothoulakis et al.	Feb 2007	A1
20070032417	Baell	Feb 2007	A1
20070037857	Perrissoud et al.	Feb 2007	A1
20070041902	Goodman et al.	Feb 2007	A1
20070060512	Sadeghi et al.	Mar 2007	A1
20070129324	Boyd et al.	Jun 2007	A1
20070161544	Wipf et al.	Jul 2007	A1
20070161551	De Luca	Jul 2007	A1
20070161690	Castro et al.	Jul 2007	A1
20070191283	Polvino	Aug 2007	A1
20070197772	Arora et al.	Aug 2007	A1
20070208061	Perrissoud et al.	Sep 2007	A2
20070238662	Mintz	Oct 2007	A1
20070274915	Rao et al.	Nov 2007	A1
20080004286	Wang et al.	Jan 2008	A1
20080015265	Rubin et al.	Jan 2008	A1
20080026993	Guyon et al.	Jan 2008	A9
20080032931	Steward et al.	Feb 2008	A1
20080081038	Cho et al.	Apr 2008	A1
20080085279	Boyd et al.	Apr 2008	A1
20080090756	Coy et al.	Apr 2008	A1
20080132485	Wang et al.	Jun 2008	A1
20080161426	Gudkov et al.	Jul 2008	A1
20080167222	Lussier et al.	Jul 2008	A1
20080171700	Nilsson et al.	Jul 2008	A1
20080194553	Gillessen et al.	Aug 2008	A1
20080194672	Hoveyda et al.	Aug 2008	A1
20080213175	Kolb et al.	Sep 2008	A1
20080234183	Hallbrink et al.	Sep 2008	A1
20080242598	Fairlie et al.	Oct 2008	A1
20080250515	Reed	Oct 2008	A1
20080260638	Rivier et al.	Oct 2008	A1
20080260820	Borrelly et al.	Oct 2008	A1
20080261873	Geesaman	Oct 2008	A1
20080262200	Nash	Oct 2008	A1
20080299040	Rivier et al.	Dec 2008	A1
20080300193	Ahn et al.	Dec 2008	A1
20080300194	Mann et al.	Dec 2008	A1
20080305490	Burrell et al.	Dec 2008	A1
20080311608	Tocque et al.	Dec 2008	A1
20090011985	Abribat et al.	Jan 2009	A1
20090047711	Nash	Feb 2009	A1
20090054331	Chen et al.	Feb 2009	A1
20090069245	Bowers et al.	Mar 2009	A1
20090081168	Sheppard et al.	Mar 2009	A1
20090088383	Abribat et al.	Apr 2009	A1
20090088553	Nash	Apr 2009	A1
20090131478	Dong et al.	May 2009	A1
20090149630	Walensky et al.	Jun 2009	A1
20090156483	Dong et al.	Jun 2009	A1
20090156795	Jaspers et al.	Jun 2009	A1
20090170757	Fraser et al.	Jul 2009	A1
20090175821	Bridon et al.	Jul 2009	A1
20090176964	Walensky et al.	Jul 2009	A1
20090198050	Marsault et al.	Aug 2009	A1
20090221512	Acosta et al.	Sep 2009	A1
20090221689	Marsault et al.	Sep 2009	A1
20090240027	Marsault et al.	Sep 2009	A1
20090253623	Abribat et al.	Oct 2009	A1
20090275511	Dong	Nov 2009	A1
20090275519	Nash et al.	Nov 2009	A1
20090275648	Fraser et al.	Nov 2009	A1
20090305300	Larsen	Dec 2009	A1
20090311174	Allen	Dec 2009	A1
20090326192	Nash et al.	Dec 2009	A1
20090326193	Maggio et al.	Dec 2009	A1
20100010065	Smith	Jan 2010	A1
20100081611	Bradner et al.	Apr 2010	A1
20100087366	Abribat et al.	Apr 2010	A1
20100087381	Polvino	Apr 2010	A1
20100093057	Beattie et al.	Apr 2010	A1
20100093086	Lin et al.	Apr 2010	A1
20100152114	Schally et al.	Jun 2010	A1
20100158923	Morimoto et al.	Jun 2010	A1
20100168388	Bernal et al.	Jul 2010	A1
20100179168	Blaney et al.	Jul 2010	A1
20100184628	Nash	Jul 2010	A1
20100184645	Verdine et al.	Jul 2010	A1
20100204118	Bevec	Aug 2010	A1
20100210515	Nash et al.	Aug 2010	A1
20100216688	Nash et al.	Aug 2010	A1
20100234563	Arora et al.	Sep 2010	A1
20100239589	Woods et al.	Sep 2010	A1
20100267636	Marsolais	Oct 2010	A1
20100273704	Korsmeyer et al.	Oct 2010	A1
20100286362	Boyd et al.	Nov 2010	A1
20100298201	Nash et al.	Nov 2010	A1
20100298393	Vanderklish et al.	Nov 2010	A1
20100303791	Francis et al.	Dec 2010	A1
20100303794	Francis et al.	Dec 2010	A1
20100323964	Vitali et al.	Dec 2010	A1
20100331343	Perrissoud et al.	Dec 2010	A1
20110020435	Maggio	Jan 2011	A1
20110021529	Lain et al.	Jan 2011	A1
20110028753	Verdine et al.	Feb 2011	A1
20110046043	Wang et al.	Feb 2011	A1
20110065915	Malcolmson et al.	Mar 2011	A1
20110097389	Sobol et al.	Apr 2011	A1
20110105389	Hoveyda et al.	May 2011	A1
20110105390	Lussier et al.	May 2011	A1
20110130331	Guyon et al.	Jun 2011	A1
20110143992	Taub et al.	Jun 2011	A1
20110144303	Nash et al.	Jun 2011	A1
20110144306	Verdine et al.	Jun 2011	A1
20110151480	Sheppard et al.	Jun 2011	A1
20110158973	Madec et al.	Jun 2011	A1
20110160135	Johnstone et al.	Jun 2011	A1
20110165137	Madec et al.	Jul 2011	A1
20110166063	Bossard et al.	Jul 2011	A1
20110171191	Johnstone et al.	Jul 2011	A1
20110183917	Lu et al.	Jul 2011	A1
20110195080	Haffer et al.	Aug 2011	A1
20110218155	Walensky et al.	Sep 2011	A1
20110223149	Nash et al.	Sep 2011	A1
20110230415	Berlanga Acosta et al.	Sep 2011	A1
20110243845	Goodman et al.	Oct 2011	A1
20110245159	Hoveyda et al.	Oct 2011	A1
20110245175	Arora et al.	Oct 2011	A1
20110245459	Marsault et al.	Oct 2011	A1
20110245477	Hoveyda et al.	Oct 2011	A1
20110250685	Nash	Oct 2011	A1
20110251252	Wang et al.	Oct 2011	A1
20110263815	Nash	Oct 2011	A1
20110269683	Rivier et al.	Nov 2011	A1
20110313167	Doemling	Dec 2011	A1
20120004174	Abribat et al.	Jan 2012	A1
20120010157	Polvino et al.	Jan 2012	A1
20120040889	Nash et al.	Feb 2012	A1
20120052548	Steward et al.	Mar 2012	A1
20120077745	Polvino	Mar 2012	A1
20120082636	Walensky et al.	Apr 2012	A1
20120083494	Aicher et al.	Apr 2012	A1
20120101047	Nash et al.	Apr 2012	A1
20120115783	Nash et al.	May 2012	A1
20120115793	Nash et al.	May 2012	A1
20120149648	Nash et al.	Jun 2012	A1
20120156197	Errico et al.	Jun 2012	A1
20120165566	Marsault et al.	Jun 2012	A1
20120172311	Nash et al.	Jul 2012	A1
20120178700	Nash et al.	Jul 2012	A1
20120190818	Nash	Jul 2012	A1
20120226066	Marsault et al.	Sep 2012	A1
20120226067	Marsault et al.	Sep 2012	A1
20120226072	Marsault et al.	Sep 2012	A1
20120238507	Fairlie et al.	Sep 2012	A1
20120264674	Nash et al.	Oct 2012	A1
20120264738	Sugimoto et al.	Oct 2012	A1
20120270800	Verdine et al.	Oct 2012	A1
20120283269	Blagosklonny et al.	Nov 2012	A1
20120328692	Lu et al.	Dec 2012	A1
20130005943	Arora et al.	Jan 2013	A1
20130023646	Nash et al.	Jan 2013	A1
20130039851	Maggio	Feb 2013	A1
20130072439	Nash et al.	Mar 2013	A1
20130096050	Shandler	Apr 2013	A1
20130123169	Kawahata et al.	May 2013	A1
20130123196	Arora et al.	May 2013	A1
20130177979	Turkson	Jul 2013	A1
20130210743	Guerlavais et al.	Aug 2013	A1
20130210745	Guerlavais et al.	Aug 2013	A1
20130211046	Verdine et al.	Aug 2013	A1
20130274205	Guerlavais et al.	Oct 2013	A1
20130330421	Marine	Dec 2013	A1
20130333419	Koketsu et al.	Dec 2013	A1
20140005118	Verdine et al.	Jan 2014	A1
20140011979	Verdine et al.	Jan 2014	A1
20140018302	Walensky et al.	Jan 2014	A1
20140051828	Arora et al.	Feb 2014	A1
20140128581	Darlak et al.	May 2014	A1
20140141980	Stephan et al.	May 2014	A1
20140162339	Verdine et al.	Jun 2014	A1
20140235549	Moellering et al.	Aug 2014	A1
20140256912	Moellering et al.	Sep 2014	A1
20140296160	Walensky et al.	Oct 2014	A1
20150051155	Guerlavais et al.	Feb 2015	A1
20150056612	Shen et al.	Feb 2015	A1
20150119551	Bernal et al.	Apr 2015	A1
20150183825	Guerlavais et al.	Jul 2015	A1
20160052970	Guerlavais et al.	Feb 2016	A1
20160122405	Palchaudhuri et al.	May 2016	A1
20160215036	Verdine et al.	Jul 2016	A1
20160244494	Verdine et al.	Aug 2016	A1
20160257725	Verdine et al.	Sep 2016	A1
20170114098	Aivado et al.	Apr 2017	A1
20170212125	Nash et al.	Jul 2017	A1
20170226177	Kawahata et al.	Aug 2017	A1
20170266254	Nash et al.	Sep 2017	A1
20170296620	Nash	Oct 2017	A1
20170298099	Nash et al.	Oct 2017	A1
20170360881	Samant et al.	Dec 2017	A1
20180085426	Nash et al.	Mar 2018	A1

Foreign Referenced Citations (256)

Number	Date	Country
2008232709	Oct 2008	AU
2700925	Apr 2009	CA
2761253	Jun 2013	CA
1252808	May 2000	CN
1583730	Feb 2005	CN
1906209	Jan 2007	CN
101244053	Aug 2008	CN
101636407	Jan 2010	CN
102223891	Oct 2011	CN
102399283	Apr 2012	CN
102399284	Apr 2012	CN
9700369	Sep 1998	CZ
0467699	Jan 1992	EP
0467699	Feb 1993	EP
0528312	Feb 1993	EP
0552417	Jul 1993	EP
0352014	Mar 1994	EP
0729972	Sep 1996	EP
0643726	Aug 1999	EP
0977580	Apr 2003	EP
1321474	Jun 2003	EP
1452868	Sep 2004	EP
1541692	Jun 2005	EP
1602663	Dec 2005	EP
1609802	Dec 2005	EP
1243923	Mar 2006	EP
1180016	Sep 2006	EP
0958305	Jun 2008	EP
2091552	Aug 2009	EP
2100901	Sep 2009	EP
2310407	Apr 2011	EP
1597585	Jun 2011	EP
2377849	Oct 2011	EP
2488193	Aug 2012	EP
2489360	Aug 2012	EP
2114428	Oct 2012	EP
2637680	Sep 2013	EP
2002524391	Aug 2002	JP
2008501623	Jan 2008	JP
2008096423	Apr 2008	JP
2010510236	Apr 2010	JP
2010518017	May 2010	JP
2010120881	Jun 2010	JP
2010519318	Jun 2010	JP
2012503025	Feb 2012	JP
WO-8909233	Oct 1989	WO
WO-8912675	Dec 1989	WO
WO-9206998	Apr 1992	WO
WO-9213878	Aug 1992	WO
WO-9301203	Jan 1993	WO
WO-9307170	Apr 1993	WO
WO-9422910	Oct 1994	WO
WO-9425482	Nov 1994	WO
WO-9500534	Jan 1995	WO
WO-9522546	Aug 1995	WO
WO-9602642	Feb 1996	WO
WO-9620951	Jul 1996	WO
WO-9628449	Sep 1996	WO
WO-9632126	Oct 1996	WO
WO-9634878	Nov 1996	WO
WO-9700267	Jan 1997	WO
WO-9713537	Apr 1997	WO
WO-9714794	Apr 1997	WO
WO-9726002	Jul 1997	WO
WO-9730072	Aug 1997	WO
WO-9737705	Oct 1997	WO
WO-9801467	Jan 1998	WO
WO-9817625	Apr 1998	WO
WO-9846631	Oct 1998	WO
WO-9847525	Oct 1998	WO
WO-9914259	Mar 1999	WO
WO-9934833	Jul 1999	WO
WO-9934850	Jul 1999	WO
WO-9963929	Dec 1999	WO
WO-0006187	Feb 2000	WO
WO-0006187	May 2000	WO
WO-02064790	Aug 2002	WO
WO-02070547	Sep 2002	WO
WO-02072597	Sep 2002	WO
WO-02064790	May 2003	WO
WO-03054000	Jul 2003	WO
WO-03059933	Jul 2003	WO
WO-03070892	Aug 2003	WO
WO-03102538	Dec 2003	WO
WO-03106491	Dec 2003	WO
WO-03059933	Jan 2004	WO
WO-2004026896	Apr 2004	WO
WO-2004037754	May 2004	WO
WO-2004041275	May 2004	WO
WO-2004058804	Jul 2004	WO
WO-2004077062	Sep 2004	WO
WO-2004037754	Oct 2004	WO
WO-03070892	Nov 2004	WO
WO-03106491	Dec 2004	WO
WO-2004077062	Jan 2005	WO
WO-2005001023	Jan 2005	WO
WO-2005007675	Jan 2005	WO
WO-2004077062	Feb 2005	WO
WO-2005012335	Feb 2005	WO
WO-2005035568	Apr 2005	WO
WO-2005040202	May 2005	WO
WO-2005044839	May 2005	WO
WO-2005040202	Jun 2005	WO
WO-2005007675	Jul 2005	WO
WO-2005044839	Jul 2005	WO
WO-2005074521	Aug 2005	WO
WO-2005085457	Sep 2005	WO
WO-2005090388	Sep 2005	WO
WO-2005097173	Oct 2005	WO
WO-2005118620	Dec 2005	WO
WO-2005118625	Dec 2005	WO
WO-2005118634	Dec 2005	WO
WO-2006009645	Jan 2006	WO
WO-2006009674	Jan 2006	WO
WO-2006042408	Apr 2006	WO
WO-2005118634	May 2006	WO
WO-2005118620	Jun 2006	WO
WO-2006078161	Jul 2006	WO
WO-2006103666	Oct 2006	WO
WO-2006137974	Dec 2006	WO
WO-2006103666	Mar 2007	WO
WO-2007141533	Dec 2007	WO
WO-2008013454	Jan 2008	WO
WO-2008014216	Jan 2008	WO
WO-2008040000	Apr 2008	WO
WO-2008045238	Apr 2008	WO
WO-2008061192	May 2008	WO
WO-2008074895	Jun 2008	WO
WO-2008076904	Jun 2008	WO
WO-2007141533	Jul 2008	WO
WO-2008061192	Jul 2008	WO
WO-2008092281	Aug 2008	WO
WO-2008095063	Aug 2008	WO
WO-2008104000	Aug 2008	WO
WO-2008106507	Sep 2008	WO
WO-2008121767	Oct 2008	WO
WO-2008130464	Oct 2008	WO
WO-2008104000	Nov 2008	WO
WO-2008137633	Nov 2008	WO
WO-2008121767	Jan 2009	WO
WO-2009009727	Jan 2009	WO
WO-2009031916	Mar 2009	WO
WO-2009033667	Mar 2009	WO
WO-2009033668	Mar 2009	WO
WO-2009042237	Apr 2009	WO
WO-2009009727	May 2009	WO
WO-2009089004	Jul 2009	WO
WO-2009033667	Aug 2009	WO
WO-2009033668	Aug 2009	WO
WO-2009099677	Aug 2009	WO
WO-2009110952	Sep 2009	WO
WO-2009126292	Oct 2009	WO
WO-2009129311	Oct 2009	WO
WO-2009137532	Nov 2009	WO
WO-2009042237	Dec 2009	WO
WO-2009149214	Dec 2009	WO
WO-2009149339	Dec 2009	WO
WO-2010011313	Jan 2010	WO
WO-2010013011	Feb 2010	WO
WO-2010033617	Mar 2010	WO
WO-2010033879	Mar 2010	WO
WO-2010034026	Mar 2010	WO
WO-2010034028	Mar 2010	WO
WO-2010034029	Mar 2010	WO
WO-2010034031	Mar 2010	WO
WO-2010034032	Mar 2010	WO
WO-2010034034	Mar 2010	WO
WO-2010058819	May 2010	WO
WO-2010060112	May 2010	WO
WO-2010065572	Jun 2010	WO
WO-2010068684	Jun 2010	WO
WO-2009129311	Jul 2010	WO
WO-2010083347	Jul 2010	WO
WO-2010083501	Jul 2010	WO
WO-2010100351	Sep 2010	WO
WO-2010107485	Sep 2010	WO
WO-2010121288	Oct 2010	WO
WO-2010132580	Nov 2010	WO
WO-2010011313	Dec 2010	WO
WO-2011005219	Jan 2011	WO
WO-2011008260	Jan 2011	WO
WO-2011008260	Mar 2011	WO
WO-2011023677	Mar 2011	WO
WO-2011038049	Mar 2011	WO
WO-2011047215	Apr 2011	WO
WO-2011060049	May 2011	WO
WO-2011061139	May 2011	WO
WO-2011076786	Jun 2011	WO
WO-2011090297	Jul 2011	WO
WO-2011101297	Aug 2011	WO
WO-2011106650	Sep 2011	WO
WO-2011133948	Oct 2011	WO
WO-2011143208	Nov 2011	WO
WO-2011143209	Nov 2011	WO
WO-2011153491	Dec 2011	WO
WO-2011159917	Dec 2011	WO
WO-2011161699	Dec 2011	WO
WO-2011162968	Dec 2011	WO
WO-2011163012	Dec 2011	WO
WO-2011133948	Jan 2012	WO
WO-2012012352	Jan 2012	WO
WO-2012016186	Feb 2012	WO
WO-2012021874	Feb 2012	WO
WO-2012021875	Feb 2012	WO
WO-2012021876	Feb 2012	WO
WO-2012033525	Mar 2012	WO
WO-2012034954	Mar 2012	WO
WO-2012037519	Mar 2012	WO
WO-2012038307	Mar 2012	WO
WO-2012040459	Mar 2012	WO
WO-2011153491	Apr 2012	WO
WO-2012045018	Apr 2012	WO
WO-2012047587	Apr 2012	WO
WO-2012051405	Apr 2012	WO
WO-2012059696	May 2012	WO
WO-2012065022	May 2012	WO
WO-2012065181	May 2012	WO
WO-2012066095	May 2012	WO
WO-2012040459	Jun 2012	WO
WO-2012076513	Jun 2012	WO
WO-2012080376	Jun 2012	WO
WO-2012080389	Jun 2012	WO
WO-2012083078	Jun 2012	WO
WO-2012083181	Jun 2012	WO
WO-2011159917	Jul 2012	WO
WO-2012094755	Jul 2012	WO
WO-2012037519	Aug 2012	WO
WO-2012121057	Sep 2012	WO
WO-2012122059	Sep 2012	WO
WO-2012149563	Nov 2012	WO
WO-2012173846	Dec 2012	WO
WO-2012174423	Dec 2012	WO
WO-2012175962	Dec 2012	WO
WO-2013033645	Mar 2013	WO
WO-2013036208	Mar 2013	WO
WO-2013049250	Apr 2013	WO
WO-2013059525	Apr 2013	WO
WO-2013059530	Apr 2013	WO
WO-2013062923	May 2013	WO
WO-2013116829	Aug 2013	WO
WO-2013123266	Aug 2013	WO
WO-2013123267	Aug 2013	WO
WO-2013166319	Nov 2013	WO
WO-2014020502	Feb 2014	WO
WO-2014047673	Apr 2014	WO
WO-2014052647	Apr 2014	WO
WO-2014055564	Apr 2014	WO
WO-2014071241	May 2014	WO
WO-2014115080	Jul 2014	WO
WO-2014134201	Sep 2014	WO
WO-2015017803	Feb 2015	WO
WO-2015097622	Jul 2015	WO
WO-2015097621	Oct 2015	WO
WO-2017165299	Sep 2017	WO
WO-2017205786	Nov 2017	WO
WO-2017218949	Dec 2017	WO

Non-Patent Literature Citations (1042)

Entry
Abbas, et al. (2010). Mdm2 is required for survival of hematopoietic stem cells/progenitors via dampening of ROS-induced p53 activity. Cell Stem Cell 7, 606-617.
Abraham, et al. (2016). Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells. Nature 534, 341-346.
Ahn, et al. A convenient method for the efficient removal of ruthenium byproducts generated during olefin metathesis reactions. Organic Letters. 2001; 3(9):1411-1413.
Akala, et al. (2008). Long-term haematopoietic reconstitution by Trp53-/-p16Ink4a-/-p19Arf-/-multipotent progenitors. Nature 453, 228-232.
Al-Lazikani, et al. Combinatorial drug therapy for cancer in the post-genomic era. Nature biotechnology 30.7 (2012): 679-692.
Andreeff, et al. (2016). Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia. Clin Cancer Res 22, 868-876.
Angel & Karin, “The Role of Jun, Fos and the AP-1 Complex in Cell-proliferation and Transformation,” Biochim. Biophys. Acta 1072:129-157 (1991).
Angell, et al. Peptidomimetics via copper-catalyzed azide-alkyne cycloadditions. Chem Soc Rev. Oct. 2007;36(10):1674-89.
Angell, et al. Ring closure to beta-turn mimics via copper-catalyzed azide/alkyne cycloadditions. J Org Chem. Nov. 11, 2005;70(23):9595-8.
Annis, et al. A general technique to rank protein-ligand binding affinities and determine allosteric versus direct binding site competition in compound mixtures. J Am Chem Soc. 2004 Dec 1;126(47):15495-503.
Annis, et al. Alis: An affinity selection-mass spectrometry system for the discovery and characterization of protein-ligand Interactions. Mass Spectrometry in Medicinal Chemistry: Applications in Drug Discovery (2007): 121-156.
Arora, “Design, Synthesis, and Properties of the Hydrogen Bond Surrogate-based Artificial Alpha-helices,” American Chemical Society Meeting, San Diego (Mar. 2005) (oral).
Arora, “Hydrogen Bond Surrogate Approach for the Synthesis of Short α-Helical Peptides,” American Chemical Society Meeting, Philadelphia (Aug. 2004) (abstract of oral presentation).
Arosio, et al. Click chemistry to functionalise peptidomimetics. Tetrahedron Letters. 2006; 47:3697-3700.
Artavanis-Tsakonas et al., Notch signaling: cell fate control and signal integration in development. Science. Apr. 30, 1999;284(5415):770-6.
Asai, et al. (2012). Necdin, a p53 target gene, regulates the quiescence and response to genotoxic stress of hematopoietic stem/progenitor cells. Blood 120, 1601-1612.
Avantaggiati, M.L. Molecular horizons of cancer therapeutics: 11th Pezcoller symposium. Biochim Biophys Acta. May 17, 2000 ;1470(3):R49-59.
Babcock, Proteins, radicals, isotopes, and mutants in photosynthetic oxygen evolution. Proc Natl Acad Sci U S A. Dec. 1, 1993;90(23):10893-5.
Badyal, et al. A Simple Method for the Quantitative Analysis of Resin Bound Thiol Groups. Tetrahedron Lett. 2001; 42:8531-33.
Balof, et al. Olefin metathesis catalysts bearing a pH-responsive NHC ligand: a feasible approach to catalyst separation from RCM products. Dalton Trans. Nov. 14, 2008;(42):5791-9. doi: 10.1039/b809793c. Epub Sep. 12, 2008.
Balthaser et al., Remodelling of the natural product fumagillol employing a reaction discovery approach. Nat Chem. Dec. 2011;3(12):969-73.
Bansal, et al. Salt selection in drug development. Pharmaceutical Technology. Mar. 2, 2008;3(32).
Barker, et al. Cyclic RGD peptide analogues as antiplatelet antithrombotics. J Med Chem. May 29, 1992;35(11):2040-8. (Abstract only).
Barreyro, et al. (2012). Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS. Blood 120, 1290-1298.
Belokon, et al. Improved procedures for the synthesis of (S)-2-[N-(N'-benzylprolyl)amino]benzophenone (BPB) and Ni(II) complexes of Schiff's bases derived from BPB and amino acids. Tetrahedron: Asymmetry, vol. 9, Issue 23, Dec. 11, 1998, pp. 4249-4252.
Berezowska; et al., “Cyclic dermorphin tetrapeptide analogues obtained via ring-closing metathesis. Acta Biochim Pol. 2006;53(1):73-6. Epub Feb. 23, 2006.”
Bernal, et al. (2010). A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell 18, 411-422.
Bernal et al., Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide. (2007) J. Am Chem Soc. 9129, 2456-2457.
Bertrand, et al. (1998). Localization of ASH1 mRNA particles in living yeast. Mol Cell 2, 437-445.
Blangetti et al., Suzuki-miyaura cross-coupling in acylation reactions, scope and recent developments.Molecules. Jan. 17, 2013;18(1):1188-213. doi:10.3390/molecules18011188.
Bo, M.D., et al. (2010). MDM4 (MDMX) is overexpressed in chronic lymphocytic leukaemia (CLL) and marks a subset of p53wild-type CLL with a poor cytotoxic response to Nutlin-3. Br J Haematol 150, 237-239.
Bock, et al. 1,2,3-Triazoles as peptide bond isosteres: synthesis and biological evaluation of cyclotetrapeptide mimics. Org Biomol Chem. Mar. 21, 2007;5(6):971-5.
Bray, Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. Sep. 2006;7(9):678-89.
Brea, et al. Synthesis of omega-(hetero)arylalkynylated alpha-amino acid by Sonogashira-type reactions in aqueous media. J Org Chem. Sep. 29, 2006;71(20):7870-3.
Brou et al., A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell. Feb. 2000;5(2):207-16.
Brunel, et al. Synthesis of constrained helical peptides by thioether ligation: application to analogs of gp41. Chemical communications. 2005;20:2552-2554.
Bueso-Ramos, et al. (1993). The human MDM-2 oncogene is overexpressed in leukemias. Blood 82, 2617-2623.
Burfield & Smithers, “Desiccant Efficiency in Solvent Drying. 3. Dipolar Aprotic Solvents,” J. Org. Chem. 43(20):3966-3968 (1978).
Burgess, et al. (2016). Clinical Overview of MDM2/X-Targeted Therapies. Front Oncol. 2016; 6: 7.
Burrage, et al. Biomimetic synthesis of lantibiotics. Chemistry. Apr. 14, 2000;6(8):1455-66.
Cai, et al. Synthesis of new potent agonistic analogs of growth hormone-releasing hormone (GHRH) and evaluation of their endocrine and cardiac activities. Peptides. 2014; 52:104-112.
Campbell, et al. N-alkylated oligoamide alpha-helical proteomimetics. Org Biomol Chem. May 21, 2010;8(10):2344-51. doi: 10.1039/c001164a. Epub Mar. 18, 2010.
Cantel, et al. Synthesis and Conformational Analysis of a Cyclic Peptide Obtained via i to i+4 Intramolecular Side-Chain to Side-Chain Azide-Alkyne 1,3-Dipolar Cycloaddition. JOC Featured Article. Published on the web May 20, 2008.
Cariello, et al. Resolution of a missense mutant in human genomic DNA by denaturing gradient gel electrophoresis and direct sequencing using in vitro DNA amplification: HPRT Munich. Am J Hum Genet. May 1988;42(5):726-34.
Carlo-Stella, et al. Use of recombinant human growth hormone (rhGH) plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) for the mobilization and collection of CD34+ cells in poor mobilizers. Blood. May 1, 2004;103(9):3287-95. Epub Jan. 15, 2004.
Carvajal, et al. (2012). E2F7, a novel target, is up-regulated by p53 and mediates DNA damage-dependent transcriptional repression. Genes Dev 26, 1533-1545.
CAS Registry No. 2176-37-6, STN Entry Date Nov. 16, 1984.
CAS Registry No. 2408-85-7, STN Entry Date Nov. 16, 1984.
CAS Registry No. 4727-05-3, STN Entry Date Nov. 16, 1984.
CAS Registry No. 561321-72-0, STN Entry Date Aug. 6, 2003.
CAS Registry No. 721918-14-5, STN Entry Date Aug. 4, 2004.
Cervini, et al. Human growth hormone-releasing hormone hGHRH(1-29)-NH2: systematic structure-activity relationship studies. J Med Chem. Feb. 26, 1998;41(5):717-27.
Chakrabartty et al., “Helix Propensities of the Amino Acids Measured in Alanine-based Peptides without Helix-stabilizing Side-chain Interactions,” Protein Sci. 3:843-852 (1994).
Chang, et al. (2013). Stapled alpha-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc Natl Acad Sci U S A 110, E3445-3454.
Chapman, et al. Trapping a folding intermediate of the alpha-helix: stabilization of the pi-helix. Biochemistry. Apr. 8, 2008;47(14):4189-95. doi: 10.1021/bi800136m. Epub Mar. 13, 2008.
Chen, et al. Determination of the Secondary Structures of Proteins by Circular Dichroism and Optical Rotatory Dispersion. Biochemistry. 1972; 11(22):4120-4131.
Chen et al., “Structure of the DNA-binding Domains from NFAT, Fos and Jun Bound Specifically to DNA,” Nature 392:42-48 (1998).
Chittenden, et al. A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. Embo J. Nov. 15, 1995;14(22):5589-96.
Chène et al., “Study of the Cytotoxic Effect of a Peptidic Inhibitor of the p53-hdm2 Interaction in Tumor Cells,” FEBS Lett. 529:293-297 (2002).
Chène, P., “Inhibiting the p53-MDM2 Interaction: An Important Target for Cancer Therapy,” Nat Rev. Cancer 3:102-109 (2003).
Cho, et al. An efficient method for removal of ruthenium byproducts from olefin metathesis reactions. Org Lett. Feb. 20, 2003;5(4):531-3.
Choi, et al. Application of azide-alkyne cycloaddition ‘click chemistry’for the synthesis of Grb2 SH2 domain-binding macrocycles. Bioorg Med Chem Lett. Oct. 15, 2006;16(20):5265-9.
Chu, et al. Peptide-formation on cysteine-containing peptide scaffolds. Orig Life Evol Biosph. Oct. 1999;29(5):441-9.
Clavier, et al. Ring-closing metathesis in biphasic BMI.PF6 ionic liquid/toluene medium: a powerful recyclable and environmentally friendly process. Chem Commun (Camb). Oct. 21, 2004;(20):2282-3. Epub Aug. 25, 2004.
Cline, et al. Effects of As(III) binding on alpha-helical structure. J Am Chem Soc. Mar. 12, 2003;125(10):2923-9.
Colacino, et al. Evaluation of the anti-influenza virus activities of 1,3,4-thiadiazol-2-ylcyanamide (LY217896) and its sodium salt. Antimicrob Agents Chemother. Nov. 1990;34(11):2156-63.
Colaluca et al., NUMB controls p53 tumour suppressor activity. Nature. Jan. 3, 2008;451(7174):76-80. doi: 10.1038/nature06412.
Conrad, et al. Ruthenium-Catalyzed Ring-Closing Metathesis: Recent Advances, Limitations and Opportunities. Current Organic Chemistry. Jan. 2006; vol. 10, No. 2, 10(2):185-202(18).
Co-pending U.S. Appl. No. 13/655442, filed Oct. 18, 2010.
Co-pending U.S. Appl. No. 15/233,796, filed Aug. 10, 2016.
Co-pending U.S. Appl. No. 15/256,130, filed Sep. 2, 2016.
Co-pending U.S. Appl. No. 15/257,807, filed Sep. 6, 2016.
Co-pending U.S. Appl. No. 15/259,947, filed Sep. 8, 2016.
Co-pending U.S. Appl. No. 15/332,492, filed Oct. 24, 2016.
Co-pending U.S. Appl. No. 15/349,478, filed Nov. 11, 2016.
Co-pending U.S. Appl. No. 15/463,826, filed Mar. 20, 2017.
Co-pending U.S. Appl. No. 15/493,301, filed Apr. 21, 2017.
Co-pending U.S. Appl. No. 15/592,517, filed May 11, 2017.
Co-pending U.S. Appl. No. 15/625,672, filed Jun. 16, 2017.
Cory et al., “The Bcl-2 Family: Roles in Cell Survival and Oncogenesis,” Oncogene 22:8590-8607 (2003).
Cotton et al. Reactivity of cytosine and thymine in single-base-pair mismatches with hydroxylamine and osmium tetroxide and its application to the study of mutations. PNAS USA 85(12):4397-401 (1988).
Cox et al., Insulin receptor expression by human prostate cancers. Prostate. Jan. 1, 2009;69(1):33-40. doi: 10.1002/pros.20852.
Coy, et al. Structural Simplification of Potent Growth Hormone-Releasing Hormone Analogs: Implications for Other Members of the VIP/GHRW PACAP Family. Annals of the New York Academy of Sciences. VIP, PACAP, Glucagon, and Related Peptides. Dec. 1996; 805:149-158.
Cummings, et al. Disrupting protein-protein interactions with non-peptidic, small molecule alpha-helix mimetics. Curr Opin Chem Biol. Jun. 2010;14(3):341-6. doi: 10.1016/j.cbpa.2010.04.001. Epub Apr. 27, 2010.
Danial et al., Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat Med. Feb. 2008;14(2):144-53. doi: 10.1038/nm1717. Epub Jan. 27, 2008.
Darnell, Transcription factors as targets for cancer therapy. Nat Rev Cancer. Oct. 2002;2(10):740-9.
Daugherty & Gellman, “A Fluorescence Assay for Leucine Zipper Dimerization: Avoiding Unintended Consequences of Fluorophore Attachment,” J. Am. Chem. Soc. 121:4325-4333 (1999).
De La O et al., Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc Natl Acad Sci U S A. Dec. 2, 2008;105(48):18907-12. doi: 10.1073/pnas.0810111105. Epub Nov. 21, 2008.
De Strooper et al., A presenilin-l-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. Apr. 8, 1999;398(6727):518-22.
Definition of Analog from http://cancerweb.ncl.ac.uk/cgi-bin/omd?query=analog. pp. 1-5. Accessed Jul. 7, 2005.
Deiters, et al. Adding amino acids with novel reactivity to the genetic code of Saccharomyces cerevisiae. J Am Chem Soc. Oct. 1, 2003;125(39):11782-3.
Del Bianco et al., Mutational and energetic studies of Notch 1 transcription complexes. J Mol Biol. Feb. 8, 2008;376(1):131-40. Epub Nov. 28, 2007.
Deng, et al. Cross-Coupling Reaction of lodo-1,2,3-triazoles Catalyzed by Palladium. Synthesis 2005(16): 2730-2738.
Dennis et al. Albumin binding as a general strategy for improving the pharmacokinetics of proteins. J Biol Chem. 277(38):35035-35043 (2002).
Dimartino et al, “A General Approach for the Stabilization of Peptide Secondary Structures,” American Chemical Society Meeting, New York (Sep. 2003) (poster).
Dombroski et al., Isolation of an active human transposable element. Science. Dec. 20, 1991;254(5039):1805-8.
Dovey et al., Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem. Jan. 2001;76(1):173-81.
Dubreuil, et al. Growth hormone-releasing factor: structural modification or protection for more potent analogs. Comb Chem High Throughput Screen. Mar. 2006;9(3):171-4.
Duronio, Insulin receptor is phosphorylated in response to treatment of HepG2 cells with insulin-like growth factor I. Biochem J. Aug. 15, 1990;270(1):27-32.
Dyson, et al. Applications of ionic liquids in synthesis and catalysis. Interface-Electrochemical Society. 2007; 16(1), 50-53.
Eckert & Kim, “Mechanisms of Viral Membrane Fusion and Its Inhibition,” Annu. Rev. Biochem. 70:777-810 (2001).
Edlund, et al. Data-driven unbiased curation of the TP53 tumor suppressor gene mutation database and validation by ultradeep sequencing of human tumors. PNAS Early Edition, pp. 1-20.
Eglen et al., The use of AlphaScreen technology in HTS: current status. Curr Chem Genomics. Feb. 25, 2008;1:2-10. doi: 10.2174/1875397300801010002.
Ellisen et al., TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. Aug. 23, 1991;66(4):649-61.
Ellman. Tissue sulfhydryl groups. Arch Biochem Biophys. May 1959;82(1):70-7.
Erlanson, et al. Facile synthesis of cyclic peptides containing di-, tri-, tetra-, and Pentasulfides. Tetrahedron Letters. 1998; 39(38):6799-6802.
European Medicines Agency, Guideline on the specification limits for residues of metal catalysts or metal regents. Feb. 2008; pp. 1-34.
European Medicines Agency (Pre-authorization Evaluation of Medicines for Human Use, London, Jan. 2007, p. 1-32).
European search report and opinion dated Feb. 9, 2012 for EP Application No. 09815315.8.
Faderl, et al. (2000). The prognostic significance of p16(INK4a)/p14(ARF) locus deletion and MDM-2 protein expression in adult acute myelogenous leukemia. Cancer 89, 1976-1982.
Felix et al. Biologically active cyclic (lactam) analogs of growth hormone-releasing factor: Effect of ring size and location on conformation and biological activity. Proceedings of the Twelfth American Peptide Symposium. p. 77-79:1991.
Feng et al. Solid-phase SN2 macrocyclization reactions to form beta-turn mimics. Org Lett. Jul. 15, 1999;1(1):121-4.
Ferdinandi, et al. Non-clinical pharmacology and safety evaluation of TH9507, a human growth hormone-releasing factor analogue. Basic Clin Pharmacol Toxicol. Jan. 2007;100(1):49-58.
File Hcaplus on STN. AN No. 1986:572318. Armstrong et al. X=Y-ZH systems as potential 1,3 dipoles. 5. Intramolecular imines of α-amino acid esthers. Tetrahedron. 1985; 41(17):3547-58. Abstract only. Abstract date Nov. 1986.
File Hcaplus on STN. AN No. 1990:532752. Burger et al. Synthesis of a-(trifluoromethyl)-substituted a-amino acids. Part 7. An efficient synthesis for a-trifluoromethyl-substituted w-carboxy a-amino acids. Chemiker-Zeitung (1990), 114(3), 101-4. Abstract only, date Oct. 1990.
File Hcaplus on STN. AN No. 1979:168009. Greenlee et al. A general synthesis of alpha-vinyl-alpha-amino acids Tetrahedron Letters (1978), (42), 3999-4002. Abstract date 1984.
Fischer, P. Peptide, Peptidomimetic, and Small-molecule Antagonists of the p53-HDM2 Protein-Protein Interaction. Int J Pept Res Ther. Mar. 2006;12(1):3-19. Epub Mar. 15, 2006.
Folkers, et al. Methods and principles in medicinal chemistry. Eds. R. Mannhold, H. Kubinyi, and H. Timmerman. Wiley-VCH, 2001.
Freedman, et al. Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha. Proc Natl Acad Sci U S A. Apr. 16, 2002;99(8):5367-72.
Friedman-Einat, et al. Target gene identification: target specific transcriptional activation by three murine homeodomain/VP16 hybrid proteins in Saccharomyces cerevisiae. J Exp Zool. Feb. 15, 1996;274(3):145-56.
Friedmann et al., RAM-induced allostery facilitates assembly of a notch pathway active transcription complex. J Biol Chem. May 23, 2008;283(21):14781-91. doi: 10.1074/jbc.M709501200. Epub Apr. 1, 2008.
Fry et al. Solution structures of cyclic and dicyclic analogues of growth hormone releasing factor as determined by two-dimensional NMR and CD spectroscopies and constrained molecular dynamics. Biopolymers. Jun. 1992;32(6):649-66.
Fryer et al., Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex. Genes Dev. Jun. 1, 2002;16(11):1397-411.
Fung et al., Delta-like 4 induces notch signaling in macrophages: implications for inflammation. Circulation. Jun. 12, 2007;115(23):2948-56. Epub May 28, 2007.
Galande, et al. Thioether side chain cyclization for helical peptide formation: inhibitors of estrogen receptor-coactivator interactions. Journal of Peptide Research. 2004; 63(3): 297-302.
Galande, et al. An effective method of on-resin disulfide bond formation in peptides. Journal of combinatorial chemistry. 2005;7(2):174-177.
Gallou, et al. A practical method for the removal of ruthenium byproducts by supercritical fluid extraction. Organic Process Research and Development. 2006; 10:937-940.
García-Echeverría et al., “Discovery of Potent Antagonists of the Interaction between Human Double Minute 2 and Tumor Suppressor p53,” J. Med. Chem. 43:3205-3208 (2000).
Garg et al., Mutations in NOTCH1 cause aortic valve disease. Nature. Sep. 8, 2005;437(7056):270-4. Epub Jul. 17, 2005.
Geistlinger & Guy, “An Inhibitor of the Interaction of Thyroid Hormone Receptor β and Glucocorticoid Interacting Protein 1,” J. Am. Chem. Soc. 123:1525-1526 (2001).
Gemperli et al., “Paralog-selective Ligands for Bcl-2 Proteins,” J. Am. Chem. Soc. 127:1596-1597 (2005).
Gentle et al., Direct production of proteins with N-terminal cysteine for site-specific conjugation. Bioconjug Chem. May.-Jun. 2004;15(3):658-63.
Glover & Harrison, “Crystal Structure of the Heterodimeric bZIP Transcription Factor c-Fos-c-Jun Bound to DNA,” Nature 373:257-261 (1995).
Goncalves, et al. On-resin cyclization of peptide ligands of the Vascular Endothelial Growth Factor Receptor 1 by copper(I)-catalyzed 1,3-dipolar azide-alkyne cycloaddition. Bioorg Med Chem Lett. Oct. 15, 2007;17(20):5590-4.
Gras-Masse, et al. Influence of helical organization on immunogenicity and antigenicity of synthetic peptides. Mol Immunol. Jul. 1988;25(7):673-8.
Gu, et al. (2002). Mutual dependence of MDM2 and MDMX in their functional inactivation of p53. J Biol Chem 277, 19251-19254.
Guerlavais, et al. Advancements in Stapled Peptide Drug Discovery & Development. Annual Reports in Medicinal Chemistry, vol. 49 49 (2014): 331-345.
Gupta et al., Long-term effects of tumor necrosis factor-alpha treatment on insulin signaling GUPTA pathway in HepG2 cells and HepG2 cells overexpressing constitutively active Akt/PKB. J Cell Biochem. Feb. 15, 2007;100(3):593-607.
Hamard, et al (2012). P53 basic C terminus regulates p53 functions through DNA binding modulation of subset of target genes. J Biol Chem 287, 22397-22407.
Hanessian, et al. Structure-based design and synthesis of macroheterocyclic peptidomimetic inhibitors of the aspartic protease beta-site amyloid precursor protein cleaving enzyme (BACE). J Med Chem. Jul. 27, 2006;49(15):4544-67.
Hara, S. et al. ‘Synthetic studies on halopeptins, anti-inflammatory cyclodepsipeptides’, Peptide Science. 2006 (vol. date 2005), 42nd, pp. 39-42.
Harrison, et al. Downsizing human, bacterial, and viral proteins to short water-stable alpha helices that maintain biological potency. Proc Natl Acad Sci U S A. Jun. 29, 2010;107(26):11686-91. doi: 10.1073/pnas.1002498107. Epub Jun. 11, 2010.
Haupt, et al. (1997). Mdm2 promotes the rapid degradation of p53. Nature 387, 296-299.
Hecht, S.M., ed. Bioorganic Chemistry: Peptides and Proteins. Oxford University Press. New York; 1998.
Hein, et al. Copper(I)-Catalyzed Cycloaddition of Organic Azides and 1-Iodoalkynes. Angew Chem Int Ed Engl. 2009;48(43):8018-21.
Henchey, et al. High specificity in protein recognition by hydrogen-bond-surrogate α-helices: selective inhibition of the p53/MDM2 complex. Chembiochem. Oct. 18, 2010;11(15):2104-7. doi: 10.1002/cbic.201000378.
Henchey, et al. Inhibition of Hypoxia Inducible Factor 1-Transcription Coactivator Interaction by a Hydrogen Bond Surrogate α-Helix. J Am Chem Soc. Jan. 27, 2010;132(3):941-3.
Hessa, et al. Recognition of transmembrane helices by the endoplasmic reticulum translocon. Nature. Jan. 27, 2005;433(7024):377-81.
Hilton et al., Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med. Mar. 2008;14(3):306-14. doi: 10.1038/nm1716. Epub Feb. 24, 2008.
Honda, et al. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. Dec. 22, 1997;420(1):25-7.
Hong, et al. Efficient removal of ruthenium byproducts from olefin metathesis products by simple aqueous extraction. Org Lett. May 10, 2007;9(10):1955-7.
Horiguchi, et al. Identification and characterization of the ER/lipid droplet-targeting sequence in 17beta-hydroxysteroid dehydrogenase type 11. Arch Biochem Biophys. Nov. 15, 2008;479(2):121-30. doi: 10.1016/j.abb.2008.08.020. Epub Sep. 10, 2008.
Horne, et al. Foldamers with heterogeneous backbones. Acc Chem Res. Oct. 2008;41(10):1399-408. doi: 10.1021/ar800009n. Epub Jul. 1, 2008.
Horne, et al. Heterocyclic peptide backbone modifications in an alpha-helical coiled coil. J Am Chem Soc. Dec. 1, 2004;126(47):15366-7.
Horne, et al. Structural and biological mimicry of protein surface recognition by alpha/beta-peptide foldamers. Proc Natl Acad Sci U S A. Sep. 1, 2009;106(35):14751-6. doi: 10.1073/pnas.0902663106. Epub Aug. 17, 2009.
Hossain, et al. Solid phase synthesis and structural analysis of novel A-chain dicarba analogs of human relaxin-3 (INSL7) that exhibit full biological activity. Org Biomol Chem. Apr. 21, 2009;7(8):1547-53. doi: 10.1039/b821882j. Epub Feb. 24, 2009.
Hunt, S. The Non-Protein Amino Acids. In: Barrett G.C., ed. Chemistry and Biochemistry of the Amino Acids. New York; Chapman and Hall; 1985.
International Preliminary Report on Patentability dated Apr. 14, 2016 for PCT/US2014/058680.
International Preliminary Report on Patentability dated Dec. 17, 2015 for PCT/US2014/41338.
International Preliminary Report on Patentability dated Dec. 23, 2015 for PCT/US2014/042329.
International Preliminary Report on Patentability for PCT/US2012/042719, dated Jan. 3, 2014.
International Preliminary Report on Patentability for PCT/US2013/062004, dated Apr. 9, 2015.
International Preliminary Report on Patentability for PCT/US2013/062929, dated Apr. 16, 2015.
International Preliminary Report on Patentability for PCT/US2014/025544, dated Sep. 24, 2015.
International search report and written opinion dated Feb. 7, 2013 for PCT Application No. US12/60913.
International search report and written opinion dated Feb. 9, 2016 for PCT Application No. PCT/US2015/052018.
International search report and written opinion dated Mar. 3, 2014 for PCT/US2013/068147.
International search report and written opinion dated May 9, 2016 for PCT Application No. PCTUS2016/023275.
International search report and written opinion dated May 18, 2010 for PCT Application No. US2009/057592.
International Search Report and Written Opinion dated Nov. 10, 2014 for PCT/US2014/41338.
International Search Report and Written Opinion dated Nov. 24, 2014 for PCT/US2014/042329.
International search report and written opinion dated Dec. 4, 2015 for PCT Application No. PCT/US2015/052031.
International search report and written opinion dated Dec. 6, 2016 for PCT Application No. PCT/US2016/050194.
International Search Report and Written Opinion for PCT/US2012/042719, dated Nov. 1, 2012.
International Search Report and Written Opinion for PCT/US2013/062004, dated Apr. 23, 2014.
International Search Report and Written Opinion for PCT/US2014/025544, dated Sep. 10, 2014.
International Search Report and Written Opinion for PCT/US2014/058680, dated Apr. 23, 2015.
International search report dated May 11, 2006 for PCT Application No. US2005/016894.
International search report dated Mar. 17, 2010 for PCT Application No. US2009-057931.
International search report dated Apr. 28, 2008 for PCT Application No. US2007/87615.
International Search Report dated Sep. 10, 2014 for PCT Application No. US2014/025544.
International search report dated Sep. 25, 2008 for PCT Application No. US2008/54922.
International search report with written opinion dated Feb. 16, 2017 for PCT/US2016/045165.
Invitation to Pay Aditional Fes for PCT/US2014/025544, dated Jul. 22, 2014.
Ishikawa, et al. (2007). Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 25, 1315-1321.
Isidro-Llobet, et al. Amino acid-protecting groups. Chem Rev. Jun. 2009;109(6):2455-504. doi: 10.1021/cr800323s.
Izdebski, et al. Synthesis and biological evaluation of superactive agonists of growth hormone-releasing hormone. Proc Natl Acad Sci USA. May 23, 1995;92(11):4872-6.
Jin, et al. Structure-based design, synthesis, and activity of peptide inhibitors of RGS4 GAP activity. Methods Enzymol. 2004;389:266-77.
Jin, et al. Structure-based design, synthesis, and pharmacologic evaluation of peptide RGS4 inhibitors. J Pept Res. Feb. 2004;63(2):141-6.
Joerger, et al. Structural biology of the tumor suppressor p53. Annu Rev Biochem. 2008;77:557-82. doi: 10.1146/annurev.biochem.77.060806.091238.
Johannesson, et al. Vinyl sulfide cyclized analogues of angiotensin II with high affinity and full agonist activity at the AT(1) receptor. J Med Chem. Apr. 25, 2002;45(9):1767-77.
Jones, et al. (1998). Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. Proc Natl Acad Sci U S A 95, 15608-15612.
Joutel et al., Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. Oct. 24, 1996;383(6602):707-10.
Jung, et al. (2013). TXNIP maintains the hematopoietic cell pool by switching the function of p53 under oxidative stress. Cell Metab 18, 75-85.
Kanan et al. Reaction discovery enabled by DNA-templated synthesis and in vitro selection. Nature. Sep. 30, 2004;431(7008):545-9.
Kandoth et al. Mutational landscape and significance across 12 major cancer types. Nature 502(7471):333-339 (2013).
Kedrowski, B.L. et al. ‘Thiazoline ring formation from 2-methylcysteines and 2-halomethylalanines’, Heterocycles. 2002, vol. 58, pp. 601-634.
Kemp et al., “Studies of N-Terminal Templates for α-Helix Formation. Synthesis and Conformational Analysis of Peptide Conjugates of (2S,5S,8S,11S)-1-Acetyl-1,4-diaza-3-keto-5-carboxy-10-thiatricyclo[2.8.1.04,8]-tridecane (Ac-Hel1-OH),” J. Org. Chem. 56:6683-6697 (1991).
Kinage, et al. Highly regio-selective synthesis of beta-amino alcohol by reaction with aniline and propylene carbonate in self solvent systems over large pore zeolite catalyst. Green and Sustainable Chem. Aug. 2011;1: 76-84.
Konishi et al Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers. Cancer Res. Sep. 1, 2007;67(17):8051-7.
Kosir, et al. Breast Cancer. Available at https://www.merckmanuals.com/home/women-s-health-issues/breast-disorders/breast-cancer. Accessed on Jun. 29, 2016.
Kovall et al., Crystal structure of the nuclear effector of Notch signaling, CSL, bound to DNA. EMBO J. Sep. 1, 2004;23(17):3441-51. Epub Aug. 5, 2004.
Kubbutat, et al. Regulation of p53 stability by Mdm2. Nature. May 15, 1997;387(6630):299-303.
Kudaj, et al. An efficient synthesis of optically pure alpha-alkyl-beta-azido- and alpha-alkyl-beta-aminoalanines via ring opening of 3-amino-3-alkyl-2-oxetanones. Tetrahedron Letters. 2007; 48:6794-6797.
Kung, et al. Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nature Medicine. 2000; 6(12):1335-1340.
Larock, A. Comprehensive Organic Transformations. VCH Publishers, (1989).
Lee, et al. Novel pyrrolopyrimidine-based α-helix mimetics: cell-permeable inhibitors of protein-protein interactions. J Am Chem Soc. Feb. 2, 2011;133(4):676-9. doi: 10.1021/ja108230s.
Lenntech BV Water Treatment Solutions. http://www.lenntech.com/periodic/elements/ru.htm.Copyright © 1998-2014.
Lenos, et al. (2012). Alternate splicing of the p53 inhibitor HDMX offers a superior prognostic biomarker than p53 mutation in human cancer. Cancer Res 72, 4074-4084.
Letai, et al. Distinct BH3 Domains Either Sensitize or Activate Mitochondrial Apoptosis, Serving as Prototype Cancer Therapeutics. Cancer Cell. 2002; 2:183-192.
Lewis et al., Apoptosis in T cell acute lymphoblastic leukemia cells after cell cycle arrest induced by pharmacological inhibition of notch signaling. Chem Biol. Feb. 2007;14(2):209-19.
Li, et al. (2012). Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 21, 266-281.
Li, et al. (2014). MDM4 overexpressed in acute myeloid leukemia patients with complex karyotype and wild-type TP53. PLoS One 9, e113088.
Li et al., Alagille syndrome is caused by mutations in human Jaggedl, which encodes a ligand for Notchl. Nat Genet. Jul. 1997;16(3):243-51.
Li, et al. Application of Olefin Metathesis in Organic Synthesis. Speciality Petrochemicals. 2007; 79-82 (in Chinese with English abstract).
Li et al., Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3. J Biol Chem. Mar. 21, 2008;283(12):8046-54. doi: 10.1074/jbc.M800170200. Epub Jan. 8, 2008.
Li et al., Notch3 signaling promotes the development of pulmonary arterial hypertension. Nat Med. Nov. 2009;15(11):1289-97. doi: 10.1038/nm.2021. Epub Oct. 25, 2009.
Li, et al. Structure-based design of thioether-bridged cyclic phosphopeptides binding to Grb2-SH2 domain. Bioorg Med Chem Lett. Mar. 10, 2003;13(5):895-9.
Li, et at. Molecular-targeted agents combination therapy for cancer: Developments and potentials. International Journal of Cancer 134.6 (2014): 1257-1269.
Lifson & Roig, “On the Theory of Helix-coil Transition in Polypeptides,” J. Chem. Phys. 34(6):1963-1974 (1961).
Lindsay et al., Rab coupling protein (RCP), a novel Rab4 and Rabll effector protein. J Biol Chem. Apr. 5, 2002;277(14):12190-9. Epub Jan. 10, 2002.
Liu, et al. (2009). The p53 tumor suppressor protein is a critical regulator of hematopoietic stem cell behavior. Cell Cycle 8, 3120-3124.
Lohmar et al. Synthese symmetrischerf ketone unter verwendung von 2-Phenyl-2-oxazolin-5-on. (α-Aminosäuren als nucleophile Acyläquivalente, IV. ) Chemische Berichte. 1980;113(12): 3706-15.
Lu et al., Both Pbxl and E2A-Pbx1 bind the DNA motif ATCAATCAA cooperatively with the products of multiple murine Hox genes, some of which are themselves oncogenes. Mol Cell Biol. Jul. 1995;15(7):3786-95.
Lu et al., Structural determinants within Pbxl that mediate cooperative DNA binding with pentapeptide-containing Hox proteins: proposal for a model of a Pbxl-Hox-DNA complex. Mol Cell Biol. Apr. 1996;16(4):1632-40.
Lubman et al., Quantitative dissection of the Notch:CSL interaction: insights into the Notch-mediated transcriptional switch. J Mol Biol. Jan. 19, 2007;365(3):577-89. Epub Oct. 3, 2006.
Luo et al., Wnt signaling and human diseases: what are the therapeutic implications? Lab Invest. Feb. 2007;87(2):97-103. Epub Jan. 8, 2007.
Madden, et al. Synthesis of cell-permeable stapled peptide dual inhibitors of the p53-Mdm2/Mdmx interactions via photoinduced cycloaddition. Bioorg Med Chem Lett. Mar. 1, 2011;21(5):1472-5. doi: 10.1016/j.bmc1.2011.01.004. Epub Jan. 7, 2011.
Makimura, et al. Reduced growth hormone secretion is associated with increased carotid intima-media thickness in obesity. The Journal of Clinical Endocrinology & Metabolism. 2009;94(12):5131-5138.
Mangold, et al. Azidoalanine mutagenicity in Salmonella: effect of homologation and alpha—Mutat Res. Feb. 1989;216(1):27-33.methyl substitution.
Marqusee & Baldwin, “Helix Stabilization by Glu- . . . Lys+ Salt Bridges in Short Peptides of De Novo Design,” Proc. Nat'l Acad. Sci. USA 84:8898-8902 (1987).
Martin, et al. Thermal [2+2] intramolecular cycloadditions of fuller-1,6-enynes. Angew Chem Int Ed Engl. Feb. 20, 2006;45(9):1439-42.
Maynard, et al. Purification technique for the removal of ruthenium from olefin metathesis reaction products. Tetrahedron Letters. 1999; 40:4137-4140.
Mayo, et al. International Union of Pharmacology. XXXV. The glucagon receptor family. Pharmacol Rev. Mar. 2003;55(1):167-94.
Mellegaard-Waetzig et al., Allylic amination via decarboxylative c-n bond formation Synlett. 2005;18:2759-2762.
Miller & Scanlan, “oNBS-SPPS: A New Method for Solid-phase Peptide Synthesis,” J. Am. Chem. Soc. 120:2690-2691 (1998).
Min, et al. Structure of an HIF-1alpha-pVHL complex: hydroxyproline recognition in signaling. Science. Jun. 7, 2002;296(5574):1886-9.
Moellering et al., Abstract 69. Computational modeling and molecular optimization of stabilized alpha-helical peptides targeting NOTCH-CSL transcriptional complexes. Nov. 2010; 8(7):30. DOI: 10.1016/S1359-6349(10)71774-2. Abstract Only, European Journal of Cancer Supplements, 2010, 8(7).
Moellering et al., Computational modeling and molecular optimization of stabilized alphahelical peptides targeting NOTCH-CSL transcriptional complexes. European Journal of Cancer Supplements Nov. 2010; 8(7):30. DOI: 10.1016/S1359-6349(10)71774-2. Abstract 69.
Morita, et al. Cyclolinopeptides B-E, new cyclic peptides from Linum usitatissimum. Tetrahedron 55.4 (1999): 967-976.
Moses, et al. The growing applications of click chemistry. Chem Soc Rev. Aug. 2007;36(8):1249-62.
Muller, P. Glossary of terms used in physical organic chemistry. Pure and Applied Chemistry, 1994, vol. 66, pp. 1077-1184.
Mulqueen et al. Synthesis of the thiazoline-based siderophore (S)-desferrithiocin. 1993;48(24):5359-5364.
Muppidi, et al. Achieving cell penetration with distance-matching cysteine cross-linkers: a facile route to cell-permeable peptide dual inhibitors of Mdm2/Mdmx. Chem Commun (Camb). Sep. 7, 2011;47(33):9396-8. doi: 10.1039/c1cc13320a. Epub Jul. 19, 2011.
Murphy, et al. Growth hormone exerts hematopoietic growth-promoting effects in vivo and partially counteracts the myelosuppressive effects of azidothymidine. Blood. Sep. 15, 1992;80(6):1443-7.
Murray, et al. Targeting protein-protein interactions: lessons from p53/MDM2. Biopolymers. 2007;88(5):657-86.
Mustapa, et al. Synthesis of a cyclic peptide containing norlanthionine: effect of the thioether bridge on peptide conformation. J Org Chem. Oct. 17, 2003;68(21):8193-8.
Myriem, V. One pot iodination click reaction: A Convenient Preparation of 5-lodo-1,4-disubstituted-1,2,3-triazole. Date unknown.
Nam et al., Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell. Mar. 10, 2006;124(5):973-83.
Nam et al., Structural requirements for assembly of the CSL.intracellular Notchl.Mastermind-like 1 transcriptional activation complex. J Biol Chem. Jun. 6, 2003;278(23):21232-9. Epub Mar. 18, 2003.
Nefedova et al., Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood. May 1, 2004 ;103(9):3503-10. Epub Dec. 11, 2003.
Ngo et al. Computational complexity, protein structure prediction and the Levinthal Paradox.In: The Protein Folding Problem and Tertiary Structure Prediction. K.Merz, Jr. and S. LeGrand, eds., 1994, pp. 491-495.
Nicole, et al. Identification of key residues for interaction of vasoactive intestinal peptide with human VPAC1 and VPAC2 receptors and development of a highly selective VPAC1 receptor agonist. Alanine scanning and molecular modeling of the peptide. J Biol Chem. Aug. 4, 2000;275(31):24003-12.
Niranjan et al., The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med. Mar. 2008;14(3):290-8. doi: 10.1038/nm1731. Epub Mar. 2, 2008.
Noah, et al. A cell-based luminescence assay is effective for high-throughput screening of potential influenza antivirals. Antiviral Res. Jan. 2007;73(1):50-9. Epub Jul. 28, 2006.
Nobuo Izimiya et al. Pepuchido Gosei no Kiso to Jikken (Fundamental of peptide synthesis and experiments, Jan. 20, 1985, p. 271.
Noguera-Troise et al., Blockade of D114 inhibits tumour growth by promoting non-productive angiogenesis. Nature. Dec. 21, 2006;444(7122):1032-7.
Notice of allowance dated May 12, 2016 for U.S. Appl. No. 14/750,649.
Notice of allowance dated Aug. 31, 2016 for U.S. Appl. No. 14/750,649.
Notice of allowance dated Jan. 7, 2015 for U.S. Appl. No. 13/370,057.
Notice of allowance dated Jan. 27, 2014 for U.S. Appl. No. 12/233,555.
Notice of allowance dated Feb. 15, 2017 for U.S. Appl. No. 14/852,368.
Notice of allowance dated Mar. 2, 2017 for U.S. Appl. No. 14/852,368.
Notice of allowance dated Mar. 22, 2010 for U.S. Appl. No. 11/148,976.
Notice of allowance dated Mar. 29, 2017 for U.S. Appl. No. 14/852,368.
Notice of allowance dated May 4, 2004 for U.S. Appl. No. 09/574,086.
Notice of allowance dated May 8, 2012 for U.S. Appl. No. 12/182,673.
Notice of allowance dated May 18, 2016 for U.S. Appl. No. 14/070,354.
Notice of allowance dated Jun. 1, 2016 for U.S. Appl. No. 14/070,354.
Notice of allowance dated Jul. 7, 2009 for U.S. Appl. No. 10/981,873.
Notice of allowance dated Jul. 19, 2016 for U.S. Appl. No. 14/068,844.
Notice of allowance dated Jul. 21, 2016 for U.S. Appl. No. 14/677,679.
Notice of Allowance dated Jul. 22, 2015 for U.S. Appl. No. 14/070,367.
Notice of allowance dated Jul. 28, 2014 for U.S. Appl. No. 13/680,905.
Notice of allowance dated Aug. 16, 2016 for U.S. Appl. No. 14/483,905.
Notice of allowance dated Sep. 14, 2015 for U.S. Appl. No. 13/350,644.
Notice of allowance dated Sep. 22, 2015 for U.S. Appl. No. 12/564,909.
Notice of allowance dated Oct. 14, 2016 for U.S. Appl. No. 14/027,064.
Notice of Allowance, dated May 30, 2013, for U.S. Appl. No. 12/593,384.
Office action dated Jan. 14, 2016 for U.S. Appl. No. 14/027,064.
Office action dated Jan. 29, 2016 for U.S. Appl. No. 14/483,905.
Office action dated Feb. 4, 2014 for U.S. Appl. No. 13/370,057.
Office action dated Feb. 5, 2016 for U.S. Appl. No. 14/068,844.
Office action dated Feb. 6, 2014 for U.S. Appl. No. 13/350,644.
Office action dated Feb. 13, 2013 for U.S. Appl. No. 12/564,909.
Office action dated Feb. 24, 2015 for U.S. Appl. No. 13/252,751.
Office action dated Mar. 3, 2017 for U.S. Appl. No. 14/460,848.
Office action dated Mar. 18, 2009 for U.S. Appl. No. 11/678,836.
Office action dated Mar. 18, 2013 for U.S. Appl. No. 13/097,930.
Office action dated Mar. 18, 2015 for U.S. Appl. No. 14/070,367.
Office action dated Apr. 17, 2017 for U.S. Appl. No. 15/287,513.
Office action dated Apr. 24, 2015 for U.S. Appl. No. 12/564,909.
Office action dated Apr. 24, 2015 for U.S. Appl. No. 13/350,644.
Office action dated Apr. 26, 2012 for U.S. Appl. No. 13/097,930.
Office action dated Apr. 28, 2016 for U.S. Appl. No. 14/677,679.
Office action dated Apr. 28, 2017 for U.S. Appl. No. 14/608,641.
Office action dated May 10, 2010 for U.S. Appl. No. 11/957,325.
Office action dated May 17, 2017 for U.S. Appl. No. 14/864,687.
Office action dated May 19, 2010 for U.S. Appl. No. 12/140,241.
Office action dated May 24, 2016 for U.S. Appl. No. 14/027,064.
Office action dated Jun. 6, 2016 for U.S. Appl. No. 14/608,641.
Office action dated Jun. 18, 2014 for U.S. Appl. No. 12/564,909.
Office action dated Jun. 18, 2015 for U.S. Appl. No. 14/068,844.
Office action dated Jun. 19, 2017 for U.S. Appl. No. 15/135,098.
Office action dated Jun. 28, 2013 for U.S. Appl. No. 13/370,057.
Office action dated Jul. 30, 2013 for U.S. Appl. No. 13/097,930.
Office action dated Aug. 10, 2009 for U.S. Appl. No. 11/957,325.
Office action dated Aug. 11, 2009 for U.S. Appl. No. 12/140,241.
Office action dated Aug. 19, 2010 for U.S. Appl. No. 12/037,041.
Office action dated Sep. 20, 2016 for U.S. Appl. No. 14/852,368.
Office action dated Oct. 4, 2016 for U.S. Appl. No. 14/864,801.
Office action dated Oct. 15, 2012 for U.S. Appl. No. 13/097,930.
Office action dated Oct. 24, 2016 for U.S. Appl. No. 14/718,288.
Office action dated Oct. 26, 2015 for U.S. Appl. No. 14/460,848.
Office action dated Oct. 27, 2016 for U.S. Appl. No. 14/864,687.
Office action dated Oct. 31, 2014 for U.S. Appl. No. 13/370,057.
Office action dated Nov. 16, 2015 for U.S. Appl. No. 14/070,354.
Office action dated Nov. 26, 2013 for U.S. Appl. No. 13/655,378.
Office action dated Dec. 7, 2015 for U.S. Appl. No. 14/677,679.
Office action dated Dec. 13, 2012 for U.S. Appl. No. 12/690,076.
Office action dated Dec. 19, 2012 for U.S. Appl. No. 13/350,644.
Office action dated May 29, 2013 for U.S. Appl. No. 13/350,644.
O'Shea et al., “Mechanism of Specificity in the Fos-Jun Oncoprotein Heterodimer,” Cell 68:699-708 (1992).
Oliner, et al. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature. Apr. 29, 1993;362(6423):857-60.
O'Neil et al., FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med. Aug. 6, 2007;204(8):1813-24. Epub Jul. 23, 2007.
Oswald et al., RBP-Jkappa/SHARP recruits CtIP/CtBP corepressors to silence Notch target genes. Mol Cell Biol. Dec. 2005;25(23):10379-90.
Palchaudhuriet al.,Differentiation induction in acute myeloid leukemia using site-specific DNA-targeting. 55th ASH Annual Meeting and Exposition. Dec. 9, 2013. Accessed at https://ash.confex.com/ash/2013/webprogram/Paper60843.html.
Palomero et al., Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med. Oct. 2007;13(10):1203-10. Epub Sep. 16, 2007.
Pangborn et al., “Safe and Convenient Procedure for Solvent Purification,” Organometallics 15:1518-1520 (1996).
Park et al., Notch3 gene amplification in ovarian cancer. Cancer Res. Jun. 15, 2006;66(12):6312-8.
Parrish et al., Perspectives on alkyl carbonates in organic synthesis. Tetrahedron, 2000; 56(42): 8207-8237.
Parthier, et al. Passing the baton in class B GPCRs: peptide hormone activation via helix induction? Trends Biochem Sci. Jun. 2009;34(6):303-10. doi: 10.1016/j.tibs.2009.02.004. Epub 2009.
Passegue, et al. (2003). Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci U S A 100 Suppl 1, 11842-11849.
Patgiri, et al. A hydrogen bond surrogate approach for stabilization of short peptide sequences in alpha-helical conformation. Acc Chem Res. Oct. 2008;41(10):1289-300. Epub Jul. 17, 2008.
Patgiri et al. An orthosteric inhibitor of the Ras-Sos interaction. Nat Chem Bio 7:585-587 (2011).
Patgiri, et al. Solid phase synthesis of hydrogen bond surrogate derived alpha-helices: resolving the case of a difficult amide coupling. Org Biomol Chem. Apr. 21, 2010;8(8):1773-6.
Pattenden, et al. Enantioselective synthesis of 2-alkyl substituted cysteines. 1993;49(10):2131-2138.
Pattenden, et al. Naturally occurring linear fused thiazoline-thiazole containing metabolites: total synthesis of (-)-didehydromirabazole A, a cytotoxic alkaloid from blue-green algae. J Chem Soc. 1993;14:1629-1636.
Peller, et al. (2003). TP53 in hematological cancer: low incidence of mutations with significant clinical relevance. Hum Mutat 21, 277-284.
Peryshkov, et al. Z-Selective olefin metathesis reactions promoted by tungsten oxo alkylidene complexes. J Am Chem Soc. Dec. 28, 2011;133(51):20754-7. doi: 10.1021/ja210349m. Epub Nov. 30, 2011.
Petros et al., “Rationale for Bcl-xL/Bad Peptide Complex Formation from Structure, Mutagenesis, and Biophysical Studies,” Protein Sci. 9:2528-2534 (2000).
Pinnix et al., Active Notchl confers a transformed phenotype to primary human melanocytes. Cancer Res. Jul. 1, 2009;69(13):5312-20. doi: 10.1158/0008-5472.CAN-08-3767. Epub Jun. 23, 2009.
Plenat, et al. [Formaldehyde fixation in the third millennium]. Ann Pathol. Feb. 2001;21(1):29-47.
Punna, et al. Head-to-tail peptide cyclodimerization by copper-catalyzed azide-alkyne cycloaddition. Angew Chem Int Ed Engl. Apr. 8, 2005;44(15):2215-20.
Qi, J., et al. (2015). HDAC8 Inhibition Specifically Targets Inv(16) Acute Myeloid Leukemic Stem Cells by Restoring p53 Acetylation. Cell Stem Cell 17, 597-610.
Qian & Schellman, “Helix-coil Theories: A Comparative Study for Finite Length Polypeptides,” J. Phys. Chem. 96:3987-3994 (1992).
Ran, et al. Double Nicking by RNA-Guided CRISPR Cas9 for Enhanced Genome Editing Specificity. Cell. Aug. 28, 2013. pii: S0092-8674(13)01015-5. doi: 10.1016/j.ce11.2013.08.021. [Epub ahead of print].
Rao et al., Inhibition of NOTCH signaling by gamma secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells. Cancer Res. Apr. 1, 2009;69(7):3060-8. doi: 10.1158/0008-5472.CAN-08-4295. Epub Mar. 24, 2009.
Reis, et al. (2016). Acute myeloid leukemia patients' clinical response to idasanutlin (RG7388) is associated with pre-treatment MDM2 protein expression in leukemic blasts. Haematologica 101, e185-188.
Remington: The Science and Practice of Pharmacy. 19th Edition, 1995.
Riddoch, et al. A solid-phase labeling strategy for the preparation of technetium and rhenium bifunctional chelate complexes and associated peptide conjugates. Bioconjug Chem. Jan.-Feb. 2006;17(1):226-35.
Ridgway et al., Inhibition of D114 signalling inhibits tumour growth by deregulating angiogenesis. Nature. Dec. 21, 2006;444(7122):1083-7.
Rink, et al. Lantibiotic Structures as Guidelines for the Design of Peptides That Can Be Modified by Lantibiotic Enzymes. Biochemistry. 2005; 44:8873-8882.
Rivlin, et al. Mutations in the p53 Tumor Suppressor Gene: Important Milestones at the Various Steps of Tumorigenesis. Genes & Cancer 2011, 2:466. Originally published online May 18, 2011.
Robberecht, et al. Structural requirements for the activation of rat anterior pituitary adenylate cyclase by growth hormone-releasing factor (GRF): discovery of (N-Ac-Tyr1, D-Arg2)-GRF(1-29)-NH2 as a GRF antagonist on membranes. Endocrinology. Nov. 1985;117(5):1759-64.
Robert, A hierarchical “nesting” approach to describe the stability of alpha helices with side-chain interactions. Biopolymers. 1990;30(3-4):335-47.
Roehrl et al., “A General Framework for Development and Data Analysis of Competitive High-throughput Screens for Small-molecule Inhibitors of Protein-Protein Interactions by Fluorescence Polarization,” Biochemistry 43:16056-16066 (2004).
Roehrl et al., “Discovery of Small-molecule Inhibitors of the NFAT-Calcineurin Interaction by Competitive High-throughput Fluorescence Polarization Screening,” Biochemistry 43:16067-16075 (2004).
Roice, et al. High Capacity Poly(ethylene glycol) Based Amino Polymers for Peptide and Organic Synthesis. QSAR & Combinatorial Science. 2004;23(8):662-673.
Rojo, et al. Macrocyclic peptidomimetic inhibitors of R-secretase (BACE): First X-ray structure of a macrocyclic peptidomimetic-BACE complex. Bioorg. Med. Chem. Lett. 2006; 16:191-195.
Roof, et al. Mechanism of action and structural requirements of constrained peptide inhibitors of RGS proteins. Chem Biol Drug Des. Apr. 2006;67(4):266-74.
Rutledge et al., “A View to a Kill: Ligands for Bcl-2 Family Proteins,” Curr. Opin. Chem. Biol. 6:479-485 (2002).
Rytting, et al. Overview of Leukemia. Available at http://www.merckmanuals.com/home/blood-disorders/leukemias/overview-of%20leukemia?qt=Leukemia&%2520alt=sh. Accessed on Jun. 29, 2016.
Saghiyan, A. S., et al., “New chiral Niii complexes of Schiffs bases of glycine and alanine for efficient asymmetric synthesis of a-amino acids,” Tedrahedron: Asymmetry 17: 455-467 (2006).
Saghiyan, et al. Novel modified (S)-N-(benzoylphenyl)-1-(3,4-dichlorobenzyl)-pyrolidine-2-carboxamide derived chiral auxiliarie for asymmetric synthesis of (S)-alpha-amino acids. Chemical Journal of Armenia. Aug. 2002; 55(3):150-161. (abstract only).
Saiki, et al. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. Jan. 29, 1988;239(4839):487-91.
Sali et al., Stabilization of protein structure by interaction of alpha-helix dipole with a charged side chain. Nature. Oct. 20, 1988;335(6192):740-3.
Samant et al. “Structure activity relationship studies of gonadotropin releasing hormone antagonists containing S-aryl/alkyl norcysteines and their oxidized derivatives,” J. Med. Chem. Apr. 3, 2007. vol. 50, No. 3, pp. 2067-2077.
Sawyer, et al. Macrocyclic a-Helical Peptide Drug Discovery. Macrocycles in Drug Discovery 40 (2014): 339-366.
Schafmeister, et al. An all-hydrocarbon cross-linking system for enhancing the helicity and metabolic stability of peptides. Journal of the American Chemical Society. 2000;122(24):5891-5892.
Scott, et al. A Solid-Phase Synthetic Route to Unnatural Amino Acids with Diverse Side-Chain Substitutions. Journal of Organic Chemistry. 2002, vol. 67, No. 9, pp. 2960-2969.
Scott et al., Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Proc Natl Acad Sci U S A. Jun. 23, 1998;95(13):7772-7.
Seebach, et al. Beta-peptidic peptidomimetics. Acc Chem Res. Oct. 2008;41(10):1366-75. doi: 10.1021/ar700263g. Epub Jun. 26, 2008.
Seebach, et al. Self-Regeneration of Stereocenters (SRS)—Applications, Limitations, and Abandonment of a Synthetic Principle. Angewandte Chemie International Edition in English. 1996;35(23-24):2708-2748.
Seebeck, et al. Ribosomal synthesis of dehydroalanine-containing peptides. J Am Chem Soc. Jun. 7, 2006;128(22):7150-1.
Seiffert et al., Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors. J Biol Chem. Nov. 3, 2000;275(44):34086-91.
Shangary, et al. Targeting the MDM2-p53 interaction for cancer therapy. Clin Cancer Res. Sep. 1, 2008;14(17):5318-24. doi: 10.1158/1078-0432.CCR-07-5136.
Sharp, et al. (1999). Stabilization of the MDM2 oncoprotein by interaction with the structurally related MDMX protein. J Biol Chem 274, 38189-38196.
Shenk, et al. Biochemical method for mapping mutational alterations in DNA with S1 nuclease: the location of deletions and temperature-sensitive mutations in simian virus 40. Proc Natl Acad Sci U S A. Mar. 1975;72(3):989-93.
Shi, et al. The role of arsenic-thiol interactions in metalloregulation of the ars operant. J Biol Chem. Apr. 19, 1996;271(16):9291-7.
Shvarts, et al. (1996). MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J 15, 5349-5357.
Singh, et al. Efficient asymmetric synthesis of (S)- and (R)-N-Fmoc-S-trityl-alpha-methylcysteine using camphorsultam as a chiral auxiliary. J Org Chem. Jun. 25, 2004;69(13):4551-4.
Singhet al.,Iridium(1)-catalyzed regio- and enantioselective allylic amidation.Tet. Lett. 2007;48 (40): 7094-7098.
Smith, et al. Design, Synthesis, and Binding Affinities of Pyrrolinone-Based Somatostatin Mimetics. Organic Letters. Jan. 8, 2005, vol. 7, No. 3, pp. 399-402, plus Supporting Information, pp. S1-S39.
Solution phase synthesis from http://www.combichemistry.com/solution_phase_synthesis.html.P.1. Accessed Aug. 6, 2009.
Sparey et al., Cyclic sulfamide gamma-secretase inhibitors. Bioorg Med Chem Lett. Oct. 1, 2005;15(19):4212-6.
Spouge, et al. Strong conformational propensities enhance t cell antigenicity. J Immunol. Jan. 1, 1987;138(1):204-12.
Stad, et al. (2000). Hdmx stabilizes Mdm2 and p53. J Biol Chem 275, 28039-28044.
Stad, et al. (2001). Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms. EMBO Rep 2, 1029-1034.
Still et al., “Rapid Chromatographic Technique for Preparative Separations with Moderate Resolution,” J. Org. Chem. 43(14):2923-2925 (1978).
Struhl et al., Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature. Apr. 8, 1999;398(6727):522-5.
Stymiest, et al. Supporting information for: Solid Phase Synthesis of Dicarba Analogs of the Biologically Active Peptide Hormone Oxytocin Using Ring Closing Metathesis. Organic Letters. 2003. 1-8.
Stymiest, et al. Synthesis of biologically active dicarba analogues of the peptide hormone oxytocin using ring-closing metathesis. Org Lett. Jan. 9, 2003;5(1):47-9.
Su, et al. In vitro stability of growth hormone releasing factor (GRF) analogs in porcine plasma. Horm Metab Res. Jan. 1991;23(1):15-21.
Suter, et al. (2011). Mammalian genes are transcribed with widely different bursting kinetics. Science 332, 472-474.
Takeishi, et al. (2013). Ablation of Fbxw7 eliminates leukemia-initiating cells by preventing quiescence. Cancer Cell 23, 347-361.
Tam, et al. Protein prosthesis: 1,5-disubstituted[1,2,3]triazoles as cis-peptide bond surrogates. J Am Chem Soc. Oct. 24, 2007;129(42):12670-1.
Tan, et al. (2014). High Mdm4 levels suppress p53 activity and enhance its half-life in acute myeloid leukaemia. Oncotarget 5, 933-943.
Tang, et al. Construction and activity of a novel GHRH analog, Pro-Pro-hGHRH(1-44)-Gly-Gly-Cys. Acta Pharmacol Sin. Nov. 2004;25(11):1464-70.
Tanimura, et al. (1999). MDM2 interacts with MDMX through their RING finger domains. FEBS Lett 447, 5-9.
Therasse, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. Feb. 2, 2000;92(3):205-16.
Thundimadathil, New Reactions with Click Chemistry. An R&D Magazine Webcast. Oct. 10, 2012. Available at http://www.rdmag.com/articles/2012/10/new-reactions-click-chemistry.
Tian et al., Linear non-competitive inhibition of solubilized human gamma-secretase by pepstatin A methylester, L685458, sulfonamides, and benzodiazepines. J Biol Chem. Aug. 30, 2002;277(35):31499-505. Epub Jun. 18, 2002.
Tian, et al. Recombinant human growth hormone promotes hematopoietic reconstitution after syngeneic bone marrow transplantation in mice. Stem Cells. 1998;16(3):193-9.
Toniolo, Conformationally restricted peptides through short-range cyclizations. Int J Pept Protein Res. Apr. 1990;35(4):287-300.
Tornoe, et al. Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J Org Chem. May 3, 2002;67(9):3057-64.
Torres, et al. Peptide tertiary structure nucleation by side-chain crosslinking with metal complexation and double “click” cycloaddition. Chembiochem. Jul. 21, 2008;9(11):1701-5.
Tsuji et al., Synthesis of γ, δ-unsaturated ketones by the intramolecular decarboxylative allylation of allyl β-keto carboxylates and alkenyl allyl carbonates catalyzed by molybdenum, nickel, and rhodium complexes. Chemistry Letters. 1984; 13(10):1721-1724.
Tsuruzoe et al., Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. Mol Cell Biol. Jan. 2001;21(1):26-38.
Turner et al., “Mitsunobu Glycosylation of Nitrobenzenesulfonamides: Novel Route to Amadori Rearrangement Products,” Tetrahedron Lett. 40:7039-7042 (1999).
Tyndall, et al. Over one hundred peptide-activated G protein-coupled receptors recognize ligands with turn structure. Chem Rev. Mar. 2005;105(3):793-826.
Tyndall et al., “Proteases Universally Recognize Beta Strands in Their Active Sites,” Chem. Rev. 105:973-999 (2005).
Ueki, et al. Improved synthesis of proline-derived Ni(II) complexes of glycine: versatile chiral equivalents of nucleophilic glycine for general asymmetric synthesis of alpha-amino acids. J Org Chem. Sep. 5, 2003;68(18):7104-7.
Ueki et al., Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase. Proc Natl Acad Sci U S A. Jan. 8, 2002;99(1):419-24. Epub Dec. 18, 2001.
Ueki et al., Positive and negative regulation of phosphoinositide 3-kinase-dependent signaling pathways by three different gene products of the p85alpha regulatory subunit. Mol Cell Biol. Nov. 2000;20(21):8035-46.
Ullman et al., Luminescent oxygen channeling immunoassay: measurement of particle binding kinetics by chemiluminescence. Proc Natl Acad Sci U S A. Jun. 7, 1994;91(12):5426-30.
Van Hoof, et al. Identification of cell surface proteins for antibody-based selection of human embryonic stem cell-derived cardiomyocytes. J Proteome Res. Mar. 5, 2010;9(3):1610-8. doi: 10.1021/pr901138a.
Van Maarseveen, et al. Efficient route to C2 symmetric heterocyclic backbone modified cyclic peptides. Org Lett. Sep. 29, 2005;7(20):4503-6.
Vassilev, et al. (2004). In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844-848.
Vera, et al. (2016). Single-Cell and Single-Molecule Analysis of Gene Expression Regulation. Annu Rev Genet 50, 267-291.
Verdine et al., Stapled peptides for intracellular drug targets. Methods Enzymol. 2012;503:3-33. doi: 10.1016/B978-0-12-396962-0.00001-X.
Vila-Perello, et al. A minimalist design approach to antimicrobial agents based on a thionin template. J Med Chem. Jan. 26, 2006;49(2):448-51.
Vu, et al. (2013). Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development. ACS Med Chem Lett 4, 466-469.
Walensky et al., A stapled BID BH3 helix directly binds and activates BAX. (2006) Mol Cell 24:199-210.
Walensky, et al. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science. 2004;305(5689):1466-1470.
Walker, et al. General method for the synthesis of cyclic peptidomimetic compounds. Tetrahedron Letters. 2001; 42(34):5801-5804.
Wang, et al. (2011). Fine-tuning p53 activity through C-terminal modification significantly contributes to HSC homeostasis and mouse radiosensitivity. Genes Dev 25, 1426-1438.
Wang, et al. BID: a novel BH3 domain-only death agonist. Genes Dev. Nov. 15, 1996;10(22):2859-69.
Wang, et al. “Click” synthesis of small molecule probes for activity-based fingerprinting of matrix metalloproteases. Chem Commun (Camb). Sep. 28, 2006;(36):3783-5.
Wang, et al. Inhibition of HIV-1 fusion 1-15 by hydrogen-bond-surrogate-based alpha helices. Angewandte Chemie International Edition. 2008; 47(10):1879-1882.
Wang et al., “Recognition of a Protein Receptor with the Hydrogen Bond Surrogate-based Artificial Alpha-helices,” American Chemical Society Meeting, San Diego (Mar. 2005) (poster).
Wang et al., “Recognition of a Protein Receptor with the Hydrogen Bond Surrogate-based Artificial Alpha-helices,” Chemical Biology Symposium, Hunter College (Jan. 2005) (poster).
Weaver et al., Transition metal-catalyzed decarboxylative allylation and benzylation reactions.Chemical Rev. Mar. 9, 2011;111(3):1846-913.
Website: http://www.onelook.com/?w=span&ls=a&loc=home_ac_span, 1 page, Retrieved on Jan. 23, 2016.
Wels, et al. Synthesis of a novel potent cyclic peptide MC4-ligand by ring-closing metathesis. Bioorg. Med. Chem. Lett. 2005; 13: 4221-4227.
Weng et al., Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. Oct. 8, 2004;306(5694):269-71.
Weng et al., Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol. Jan. 2003;23(2):655-64.
Wenninger, et al. International Cosmetic Ingredient Dictionary and Handbook. vol. 2, 7th Edition, 1997, published by the Cosmetic, Toiletry, and Fragrance Association.
Westhoff et al., Alterations of the Notch pathway in lung cancer. Proc Natl Acad Sci U S A. Dec. 29, 2009;106(52):22293-8. doi: 10.1073/pnas.0907781106. Epub Dec. 10, 2009.
Wikipedia the Free Encyclopedia. Willgerodt Rearrangement. Available at https://en.wikipedia.org/wiki/Willgerodt_rearrangement. Accessed on Feb. 12, 2013.
Williams et al., Asymmetric synthesis of 2,6-diamino-6-(hydroxymethyl)pimelic acid: assignment of stereochemistry. J Am Chem Soc. 1991;113(18):6976-6981.
Wilson et al., Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA. Cell. Mar. 10, 2006;124(5):985-96.
Wu et al., MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat Genet. Dec. 2000;26(4):484-9.
Wu, et al. Studies on New Strategies for the Synthesis of Oligomeric 1,2,3-Triazoles. Synlett 2006(4): 0645-0647.
Wu et al., Therapeutic antibody targeting of individual Notch receptors. Nature. Apr. 15, 2010;464(7291):1052-7. doi: 10.1038/nature08878.
Wuts, et al. Protective Groups in Organic Synthesis. 2nd Ed., John Wiley and Songs (1991).
Xiong, et al. (2010). Spontaneous tumorigenesis in mice overexpressing the p53-negative regulator Mdm4. Cancer Res 70, 7148-7154.
Yang, et al. Calculation of protein conformation from circular dichroism. Methods Enzymol. 1986;130:208-69.
Ye et al., Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature. Apr. 8, 1999;398(6727):525-9.
Yee, et al. Efficient large-scale synthesis of BILN 2061, a potent HCV protease inhibitor, by a convergent approach based on ring-closing metathesis. J Org Chem. Sep. 15, 2006;71(19):7133-45.
Yin et al., “Terphenyl-based Helical Mimetics That Disrupt the p53/HDM2 Interaction,” Angew. Chem. Int. Ed. 44:2704-2707 (2005).
Yu, et al. Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis. Nature. Nov. 2, 2011;479(7371):88-93. doi: 10.1038/nature10563.
Zeisig, et al. (2012). SnapShot: Acute myeloid leukemia. Cancer Cell 22, 698-698 e691.
Zhang et al., A cell-penetrating helical peptide as a potential HIV-1 inhibitor. J Mol Biol. May 2, 2008;378(3):565-80. doi: 10.1016/j jmb.2008.02.066. Epub Mar. 6, 2008.
Zhang, et al. A triazole-templated ring-closing metathesis for constructing novel fused and bridged triazoles. Chem Commun (Camb). Jun. 21, 2007;(23):2420-2.
Zhang, et al. Development of a High-throughput Fluorescence Polarization Assay for Bcl-xL. Anal. Biochem. 2002; 307:70-75.
Zhang, et al. Targeting p53-MDM2-MDMX loop for cancer therapy. Subcell Biochem. 2014;85:281-319. doi: 10.1007/978-94-017-9211-0_16.
Zhao, et al. (2010). p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewal. Genes Dev 24, 1389-1402.
Zhao, et al. (2015). Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment. J Med Chem 58, 1038-1052.
Zitzow, et al. Pathogenesis of avian influenza A (H5N1) viruses in ferrets. J Virol. May 2002;76(9):4420-9.
Adhikary et al., Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol. Aug. 2005;6(8):635-45.
Agola et al., Rab GTPases as regulators of endocytosis, targets of disease and therapeutic opportunities. Clin Genet. Oct. 2011; 80(4): 305-318.
Altschul et al. Basic local alignment search tool. J Mol Biol215(3):403-410 (1990).
Aman et al., cDNA cloning and characterization of the human interleukin 13 receptor alpha chain. J Biol Chem. Nov. 15, 1996;271(46):29265-70.
Andrews et al. Forming Stable Helical Peptide Using Natural and Artificial Amino Acids. Tetrahedron. 1999;55:11711-11743.
Andrews et al., Kinetic analysis of the interleukin-13 receptor complex. J Biol Chem. Nov. 29, 2002 ;277(48):46073-8. Epub Sep. 26, 2002.
Annis, et al. A general technique to rank protein-ligand binding affinities and determine allosteric versus direct binding site competition in compound mixtures. J Am Chem Soc. Dec. 1, 2004;126(47):15495-503.
Annis, et al. ALIS: An Affinity Selection-Mass Spectrometry System for the Discovery and Characterization of Protein-Ligand Interactions. In: Wanner, K. and Höfner, G. eds. Mass Spectrometry in Medicinal Chemistry. Wiley-VCH; 2007:121-156.
Armstrong et al., X = Y-ZH Systems as potential 1,3-dipoles. 5. Intramolecular cycloadditions of imines of a-amino acid esters. Tetrahedron. 1985;41(17):3547-58.
Attisano et al., TGFbeta and Wnt pathway cross-talk. Cancer Metastasis Rev. Jan.-Jun. 2004;23(1-2):53-61.
Austin et al., “A Template for Stabilization of a Peptide α-Helix: Synthesis and Evaluation of Conformational Effects by Circular Dichroism and NMR,” J. Am. Chem. Soc. 119:6461-6472 (1997).
Babine et aL, Molecular Recognition of Proteinminus signLigand Complexes: Applications to Drug Design. Chem Rev. Aug. 5, 1997;97(5):1359-1472.
Baek, et al. Structure of the stapled p53 peptide bound to Mdm2. J Am Chem Soc. Jan. 11, 2012;134(1):103-6. doi: 10.1021/ja2090367. Epub Dec. 14, 2011.
Baell, J.B. Prospects for Targeting the Bcl-2 Family of Proteins to Develop Novel cytotoxic drugs. Biochem Pharmacol. Sep. 2002;64(5-6):851-63.
Bakhshi, et al. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell. Jul. 1985;41(3):899-906.
Banerjee et aL, Structure of a DNA glycosylase searching for lesions. Science. Feb. 24, 2006;311(5764):1153-7.
Banerjee et al., Structure of a repair enzyme interrogating undamaged DNA elucidates recognition of damaged DNA. Nature. Mar. 31, 2005;434(7033):612-8.
Banerji et al. Synthesis of Cyclic β-Turn Mimics from L-Pro-Phe/Phe-L-Pro Derived Di- and Tripeptides via Ring Closing Metathesis: The Role of Chirality of the Phe Residue During Cyclization. Tetrahedron Lett. 2002; 43:6473-6477.
Bang et al., Total chemical synthesis of crambin. J Am Chem Soc. Feb. 11, 2004;126(5):1377-83.
Barandon et al., Reduction of infarct size and prevention of cardiac rupture in transgenic mice overexpressing FrzA. Circulation. Nov. 4, 2003;108(18):2282-9. Epub Oct. 27, 2003.
Barker et al., Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov. Dec. 2006;5(12):997-1014.
Belokon et al., Chiral Complexes of Ni(II), Cu(II) and Cu(I) as Reagents, Catalysts and Receptors for Asymmetric Synthesis and Chiral Recognition of Amino Acids. Pure & Appl Chem. 1992;64(12):1917-24.
Belokon et al., Improved procedures for the synthesis of (S)-21N-(N′-benzyl-prolypaminolbenzophenone (BPB) and Ni(II) complexes of Schiff's bases derived from BPB and amino acids. Tetrahedron: Asymmetry. 1998;9:4249-52.
Bennett, et al. Regulation of osteoblastogenesis and bone mass by Wntl Ob. Proc Natl Acad Sci U S A. Mar. 1, 2005;102(9):3324-9.. Epub Feb. 22, 2005.
Berendsen et al., A glimpse of the Holy Grail? Science. Oct. 23, 1998;282(5389):642-3.
Berge et al. Pharmaceutical Salts. Journal of Pharmaceutical Sciences 66(1):1-19 (Jan. 1977).
Bernal, et al. A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell. Nov. 16, 2010;18(5):411-22. doi: 10.1016/j.ccr.2010.10.024.
Bernal, et al. Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide. J Am Chem Soc. Mar. 7, 2007;129(9):2456-7.
Biagini et al., Cross-metathesis of Unsaturated a-amino Acid Derivatives. J Chem Soc Perkin Trans. 1998;1:2485-99.
Bierzynski et al. A salt bridge stabilizes the helix formed by isolated C-Peptide of RNase A. PNAS USA. 1982;79:2470-2474.
Blackwell, et al. Highly Efficient Synthesis of Covalently Cross-Linked Peptide Helices by Ring-Closing Metathesis. Angewandte Chemie International Edition. 1998; 37(23):3281-3284.
Blackwell, et al. Ring-closing metathesis of olefinic peptides: design, synthesis, and structural characterization of macrocyclic helical peptides. J Org Chem. Aug. 10, 2001;66(16):5291-302.
Blundell et al., Atomic positions in rhombohedral 2-zinc insulin crystals. Nature. Jun. 25, 1971;231(5304):506-11.
Bode et al., Chemoselective amide ligations by decarboxylative condensations of N-alkylhydroxylamines and alpha-ketoacids. Angew Chem Int Ed Engl. Feb. 13, 2006;45(8):1248-52.
Boguslavsky, et al. Effect of peptide conformation on membrane permeability. J Pept Res. Jun. 2003;61(6):287-97.
Bossy-Wetzel et al. Assays for cytochrome c release from mitochondria during apoptosis. Methods Enzymol. 322:235-242 (2000).
Bossy-Wetzel, et al. Detection of apoptosis by annexin V labeling. Methods Enzymol. 2000;322:15-8.
Bottger, et al. Molecular characterization of the hdm2-p53 interaction. J Mol Biol. Jun. 27, 1997;269(5):744-56.
Boyden et al., High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. May. 16, 2002;346(20):1513-21.
Bracken et al. Synthesis and nuclear magnetic resonance structure determination of an alpha-helical, bicyclic, lactam-bridged hexapeptide. JACS. 1994;116:6431-6432.
Bradley et al., Limits of cooperativity in a structurally modular protein: response of the Notch ankyrin domain to analogous alanine substitutions in each repeat. J Mol Biol. Nov. 22, 2002 ;324(2):373-86.
Brandt et al., Dimeric fragment of the insulin receptor alpha-subunit binds insulin with full holoreceptor affinity. J Biol Chem. Apr. 13, 2001;276(15):12378-84. Epub Jan. 12, 2001.
Brown, et al. A spiroligomer α-helix mimic that binds HDM2, penetrates human cells and stabilizes HDM2 in cell culture. PLoS One. 2012;7(10):e45948. doi: 10.1371/journal.pone.0045948. Epub Oct. 18, 2012.
Brown, et al. Stapled peptides with improved potency and specificity that activate p53. ACS Chem Biol. Mar. 15, 2013;8(3):506-12. doi: 10.1021/cb3005148. Epub Dec. 18, 2012.
Brubaker et al., Solution structure of the interacting domains of the Mad-Sin3 complex: implications for recruitment of a chromatin-modifying complex. Cell. Nov. 10, 2000;103(4):655-65.
Brunel, et al. Synthesis of constrained helical peptides by thioether ligation: application to analogs of gp41. Chem Commun (Camb). May 28, 2005;(20):2552-4. Epub Mar. 11, 2005.
Brusselle et al., Allergen-induced airway inflammation and bronchial responsiveness in wild-type and interleukin-4-deficient mice. Am J Respir Cell Mol Biol. Mar. 1995;12(3):254.-9.
Burger et aL, Synthesis of a-(trifluoromethyl)-substituted a-amino acids. Part 7. An efficient synthesis for a-trifluoromethyl-substituted w-carboxy a-amino acids. Chemiker-Zeitung. 1990;114(3):101-04. German.
Cabezas & Satterthwait, “The Hydrogen Bond Mimic Approach: Solid-phase Synthesis of a Peptide Stabilized as an α-Helix with a Hydrazone Link,” J. Am. Chem. Soc. 121:3862-3875 (1999).
Caricasole et al., The Wnt pathway, cell-cycle activation and beta-amyloid: novel therapeutic strategies in Alzheimer's disease? Trends Pharmacol Sci. May 2003;24(5):233-8.
Carillo et al., The Multiple Sequence Alignment Problem in Biology. SIAM J Applied Math. 1988;48:1073-82.
Carlson et al., Specificity landscapes of DNA binding molecules elucidate biological function. Proc Natl Acad Sci USA. Mar. 9, 2010;107(10):4544-9. doi: 10.1073/pnas.0914023107. Epub Feb. 22, 2010.
Chakrabartty et al., “Helix Capping Propensities in Peptides Parallel Those in Proteins,” Proc. Nat'l Acad. Sci. USA 90:11332-11336 (1993).
Chang, et al. Stapled α-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc Natl Acad Sci U S A. Sep. 3, 2013;110(36):E3445-54. doi: 10.1073/pnas.1303002110. Epub Aug. 14, 2013.
Chapman et al., “A Highly Stable Short α-Helix Constrained by a Main-chain Hydrogen-bond Surrogate,” J. Am. Chem. Soc. 126:12252-12253 (2004).
Chapman, et al. Optimized synthesis of hydrogen-bond surrogate helices: surprising effects of microwave heating on the activity of Grubbs catalysts. Org Lett. Dec. 7, 2006;8(25):5825-8.
Chen et al., Determination of the helix and beta form of proteins in aqueous solution by circular dichroism. Biochemistry. Jul. 30, 1974;13(16):3350-9.
Chen et al., Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol. Feb. 2009;5(2):100-7. Epub Jan. 4, 2009.
Cheng et al., Emerging role of RAB GTPases in cancer and human disease. Cancer Res. Apr. 1, 2005;65(7):2516-9.
Cheng et al., The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers. Nat Med. Nov. 2004;10(11):1251-6. Epub Oct. 24, 2004.
Cheon et al., Beta-Catenin stabilization dysregulates mesenchymal cell proliferation, motility, and invasiveness and causes aggressive fibromatosis and hyperplastic cutaneous wounds. Proc Natl Acad Sci U S A. May 14, 2002;99(10):6973-8. Epub Apr. 30, 2002.
Chia et al., Emerging roles for Rab family GTPases in human cancer. Biochim Biophys Acta. Apr. 2009; 1795(2):110-6.
Chiaramonte et al., Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosis. Hepatology. Aug. 2001;34(2):273-82.
Chin & Schepartz, “Design and Evolution of a Miniature Bcl-2 Binding Protein,” Angew. Chem. Int. Ed. 40(20):3806-3809 (2001).
Chin et al., “Circular Dichroism Spectra of Short, Fixed-nucleus Alanine Helices,” Proc. Nat'l Acad. Sci. USA 99(24):15416-15421 (2002).
Christodoulides et al., WNT1OB mutations in human obesity. Diabetologia. Apr. 2006;49(4):678-84. Epub Feb. 14, 2006.
Clark et al., Supramolecular Design by Covalent Capture. Design of a Peptide Cylinder via Hydrogen-Bond-Promoted Intermolecular Olefin Metathesis. J Am Chem Soc. 1995;117:12364-65.
Cleary, et al. Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18. Proc Natl Acad Sci U S A. Nov. 1985;82(21):7439-43.
Clevers, Wnt/beta-catenin signaling in development and disease. Cell. Nov. 3, 2006;127(3):469-80.
Cohn et al., Cutting Edge: IL-4-independent induction of airway hyperresponsiveness by Th2, but not Thl, cells. J Immunol. Oct. 15, 1998;161(8):3813-6.
Cole et al., Transcription-independent functions of MYC: regulation of translation and DNA replication. Nat Rev Mol Cell Biol. Oct. 2008;9(10):810-5. Epub Aug. 13, 2008.
Cong et al., A protein knockdown strategy to study the function of beta-catenin in tumorigenesis. BMC Mol Biol. Sep. 29, 2003;4:10.
Co-pending U.S. Appl. No. 13/494,846, filed Jun. 12, 2012.
Cossu et al., Wnt signaling and the activation of myogenesis in mammals EMBO J. Dec. 15, 1999;18(24):6867-72.
Cusack et al. 2,4,6-Tri-isopropylbenzenesulphonyl Hydrazide: A convenient source of Di-Imide. Tetrahedron. 1976;32:2157-2162.
Danial, et al. Cell death: critical control points. Cell. 2004; 116:204-219.
David et al., Expressed protein ligation. Method and applications. Eur J Biochem. Feb. 2004;271(4):663-77.
Dawson et al., Synthesis of proteins by native chemical ligation. Science. Nov. 4, 1994;266(5186):776-9.
De Guzman et al., Structural basis for cooperative transcription factor binding to the CBP coactivator. J Mol Biol. Feb. 3, 2006;355(5):1005-13. Epub Oct. 5, 2005.
De Meyts et al., Insulin interactions with its receptors: experimental evidence for negative cooperativity. Biochem Biophys Res Commun. Nov. 1, 1973;55(1):154-61.
De Meyts, The structural basis of insulin and insulin-like growth factor-I receptor binding and negative co-operativity, and its relevance to mitogenic versus metabolic signalling. Diabetologia. Sep. 1994;37 Suppl 2:S135-48.
Debinski et al., Retargeting interleukin 13 for radioimmunodetection and radioimmunotherapy of human high-grade gliomas. Clin Cancer Res. Oct. 1999;5(10 Suppl):3143s-3147s.
Degterev et al. Identification of Small-molecule Inhibitors of Interaction between the BH3 Domain and Bcl-xL. Nature Cell Biol. 3:173-182 (2001).
Denmark et al., Cyclopropanation with Diazomethane and Bis(oxazoline)palladium(II) Complexes. J Org Chem. May 16, 1997;62(10):3375-3389.
Designing Custom Peptide. from SIGMA Genosys, pp. 1-2. Accessed Dec. 16, 2004.
Devereux et al., A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. Jan. 11, 1984;12(1 Pt 1):387-95.
Dimartino et al. Solid-phase synthesis of hydrogen-bond surrogate-derived alpha-helices. Org Lett. Jun. 9, 2005;7(12):2389-92.
Doron, et al. Probiotics: their role in the treatment and prevention of disease. Expert Rev Anti Infect Ther. Apr. 2006;4(2):261-75.
Eisenmesser et al., Solution structure of interleukin-13 and insights into receptor engagement. J Mol Biol. Jun. 29, 2001;310(1):231-41.
Ellis et al., Design, synthesis, and evaluation of a new generation of modular nucleophilic glycine equivalents for the efficient synthesis of sterically constrained alpha-amino acids. J Org Chem. Oct. 27, 2006;71(22):8572-8.
Erlanson et al., The leucine zipper domain controls the orientation of AP-1 in the NFAT.AP-1.DNA complex. Chem Biol. Dec. 1996;3(12):981-91.
European office action dated Aug. 20, 2012 for EP Application No. 09730445.5.
European search report and search opinion dated May 6, 2011 for Application No. 10195495.6.
European search report and search opinion dated May 9, 2011 for Application No. 10195490.7.
European search report and search opinion dated Sep. 30, 3015 for EP Application No. 13749501-6.
European search report and search opinion dated Oct. 5, 2015 for EP Application No. 13748983-7.
European search report dated Nov. 7, 2008 for Application No. 8016651.5.
European search report dated Aug. 22, 2008 for Application No. 4811198.3.
Evans et al., The Rise of Azide—Alkyne 1,3-Dipolar ‘Click’ Cycloaddition and its Application to Polymer Science and Surface Modification. Australian Journal of Chemistry. 2007;60:384-95.
Extended European Search Report for EP 09800675.2, dated Dec. 6, 2012.
Extended European Search Report for EP 10800148.8, dated Oct. 16, 2013.
Extended European Search Report for EP 12159110.1, dated Jul. 20, 2012.
Extended European Search Report for EP 12159110 1, dated Sep. 27, 2012.
Favrin et al., Two-state folding over a weak free-energy barrier. Biophys J. Sep. 2003;85(3):1457-65.
Felix et al., “Synthesis, Biological Activity and Conformational Analysis of Cyclic GRF Analogs,” Int. J. Pep. Protein Res. 32:441-454 (1988).
Fields, et al. Chapter 3 in Synthetic Peptides: A User's Guide. Grant W.H. Freeman & Co. New York, NY. 1992. p. 77.
Fieser, et al. Fieser and Fieser's Reagents for Organic Synthesis. John Wiley and Sons. 1994.
Fischback et al., Specific biochemical inactivation of oncogenic Ras proteins by nucleoside diphosphate kinase. Cancer Res. Jul. 15, 2003;63(14):4089-94.
Fischer, et al. Apoptosis-based therapies and drug targets. Cell Death and Differentiation. 2005; 12:942-961.
Fischer et al., The HIV-1 Rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs. Cell. Aug. 11, 1995;82(3):475-83.
Fisher et al., Myc/Max and other helix-loop-helix/leucine zipper proteins bend DNA toward the minor groove. Proc Natl Acad Sci U S A. Dec. 15, 1992;89(24):11779-83.
Formaggio et al., Inversion of 3(10)-helix screw sense in a (D-alpha Me)Leu homo-tetrapeptide induced by a guest D-(alpha Me)Val residue. J Pept Sci. Nov.-Dec. 1995;1(6):396-402.
Fromme et al., Structural basis for removal of adenine mispaired with 8-oxoguanine by MutY adenine DNA glycosylase. Nature. Feb. 12, 2004;427(6975):652-6.
Fuchs et al., Socializing with the neighbors: stem cells and their niche. Cell. Mar. 19, 2004;116(6):769-78.
Fulda, et al. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. Aug. 7, 2006;25(34):4798-811.
Furstner et al., Alkyne Metathesis: Development of a Novel Molybdenum-Based Catalyst System and Its Application to the Total Synthesis of Epothilone A and C. Chem Euro J. 2001;7(24):5299-5317.
Furstner, et al. Mo[N(t-Bu)(AR)]3 Complexes as catalyst precursors: In situ activation and application to metathesis reactions of alkynes and diynes. J Am chem Soc. 1999; 121:9453-54.
Furstner, et al. Nozaki—Hiyama—Kishi reactions catalytic in chromium. J Am Chem Soc. 1996; 118:12349-57.
“Fustero, et al. Asymmetric synthesis of new beta,beta-difluorinated cyclic quaternary alpha-amino acid derivatives. Org Lett. Aug. 31, 2006;8(18):4129-32.”
Galande, et al. An effective method of on-resin disulfide bond formation in peptides. J Comb Chem. Mar.-Apr. 2005;7(2):174-7.
Gallivan et al., A neutral, water-soluble olefin metathesis catalyst based on an N-heterocyclic carbene ligand. Tetrahedron Letters. 2005;46:2577-80.
Galluzzi, et al. Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes. Cell Death Differ. Aug. 2009;16(8):1093-107. Epub Apr. 17, 2009.
Gante, Peptidomimetics—Tailored Enzyme Inhibitors. J Angew Chem Int Ed Engl. 1994;33:1699-1720.
Gat et al., De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell. Nov. 25, 1998;95(5):605-14.
Gavathiotis et al., BAX activation is initiated at a novel interaction site. Nature. Oct. 23, 2008;455(7216):1076-81.
Gerber-Lemaire et al., Glycosylation pathways as drug targets for cancer: glycosidase inhibitors. Mini Rev Med Chem. Sep. 2006;6(9):1043-52.
Ghadiri & Choi, “Secondary Structure Nucleation in Peptides. Transition Metal Ion Stabilized α-Helices,” J. Am. Chem. Soc. 112:1630-1632 (1990).
Giannis et aL, Peptidomimetics for Receptor Ligands—Discovery, Development, and Medical Perspectives. Angew Chem Int Ed Engl. 1993;32:1244-67.
Gong et al., LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. Nov. 16, 2001;107(4):513-23.
Goodson et al., Potential Growth Antagonists. I. Hydantoins and Disubstituted Glycines. J Org Chem. 1960;25:1920-24.
Gorlich et al., Transport between the cell nucleus and the cytoplasm. Annu Rev Cell Dev Biol. 1999;15:607-60.
Goun et al., Molecular transporters: synthesis of oligoguanidinium transporters and their application to drug delivery and real-time imaging. Chembiochem. Oct. 2006;7(10):1497-515.
Greene, et al. Protective Groups in Organic Synthesis, 2nd Ed. John Wiley and Sons. 1991.
Greenfield et al. Computed circular dichroism spectra for the evaluation of protein conformation. Biochemistry. Oct, 8. 1969;(10):4108-4116.
Greenlee et al., A General Synthesis of a-vinyl-a-amino acids. Tetrahedron Letters. 1978;42:3999-40002.
Grossman, et al. Inhibition of oncogenic Wnt signaling through direct targeting of -catenin. Proc. Natl. Acad. Sco. 2012; 109(44):17942-179747.
Grubbs, et al. Ring-Closing Metathesis and Related Processes in Organic Synthesis. Acc. Chem. Res., 1995, 28 (11), pp. 446-452.
Grunig et al., Requirement for IL-13 independently of IL-4 in experimental asthma. Science. Dec. 18, 1998;282(5397):2261-3.
Guinn et al., Synthesis and characterization of polyamides containing unnatural amino acids. Biopolymers. May 1995;35(5):503-12.
Guo et al., Probing the alpha-helical structural stability of stapled p53 peptides: molecular dynamics simulations and analysis. Chem Biol Drug Des. Apr. 2010;75(4):348-59. doi: 10.1111/j.1747-0285.2010.00951.x.
Harper et al., Efficacy of a bivalent LI virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomized controlled trial. Lancet. Nov. 13-19, 2004;364(9447):1757-65.
Harris et al., Synthesis of proline-modified analogues of the neuroprotective agent glycyl-I-prolyl-glutamic acid (GPE). Tetrahedron. 2005;61:10018-35.
Hartmann, A Wnt canon orchestrating osteoblastogenesis. Trends Cell Biol. Mar. 2006;16(3):151-8. Epub Feb. 7, 2006.
Hartmann et al., Dual roles of Wnt signaling during chondrogenesis in the chicken limb. Development. Jul. 2000;127(14):3141-59.
Hase; et al., “1,6-Aminosuberic acid analogs of lysine- and arginine-vasopressin and -vasotocin. Synthesis and biological properties. J Am Chem Soc. May 17, 1972;94(10):3590-600.”
Hellman et al., Electrophoretic mobility shift assay (EMSA) for detecting protein-nucleic acid interactions. Nat Protoc. 2007;2(8):1849-61.
Henchey et al., Contemporary strategies for the stabilization of peptides in the a-helical conformation. Curr Opin Chem Biol. 2008;12:692-97.
Hipfner et al., Connecting proliferation and apoptosis in development and disease. Nat Rev Mol Cell Biol. Oct. 2004;5(10):805-15.
Hiroshige, et al. Palladium-mediated macrocyclisations on solid support and its applica-tions to combinatorial synthesis. J. Am. Chem. Soc. 1995; 117:11590-11591.
Hoang et al., Dickkopf 3 inhibits invasion and motility of Saos-2 osteosarcoma cells by modulating the Wnt-beta-catenin pathway. Cancer Res. Apr. 15, 2004;64(8):2734-9.
Holford et al., Adding ‘splice’ to protein engineering. Structure. Aug. 15, 1998;6(8):951-6.
Hoveyda et al., “Ru Complexes Bearing Bidentate Carbenes: From Innocent Curiosity to Uniquely Effective Catalysts for Olefin Metathesis,” Org. Biomolec. Chem. 2:8-23 (2004).
Hu, et al. Efficient p53 activation and apoptosis by simultaneous disruption of binding to MDM2 and MDMX. Cancer Res. Sep. 15, 2007;67(18):8810-7.
Huang et al., How insulin binds: the B-chain alpha-helix contacts the Li beta-helix of the insulin receptor. J Mol Biol. Aug. 6, 2004;341(2):529-50.
Huang et al., Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature. Oct. 1, 2009;461(7264):614-20. Epub Sep. 16, 2009.
International Preliminary Repoert on Patentability for PCT/US2011/052755, dated Apr. 4, 2013.
International Preliminary Report on Patentability for PCT/US2008/058575 dated Oct. 8, 2009.
International Preliminary Report on Patentability for PCT/US2009/004260 dated Feb. 3, 2011.
International Preliminary Report on Patentability for PCT/US2010/001952 dated Jan. 26, 2012.
International Preliminary Report on Patentability for PCT/US2012/042738, dated Jan. 3, 2014.
International search report and written opinion dated May 23, 2013 for PCT/US2013/026241.
International search report and written opinion dated May 29, 2013 for PCT/US2013/026238.
International search report and written opinion dated Oct. 12, 2011 for PCT/US2011/047692.
International Search Report and Written Opinion for PCT/US2008/052580, dated May 16, 2008.
International Search Report and Written Opinion for PCT/US2008/058575 dated Nov. 17, 2008.
International Search Report and Written Opinion for PCT/US2009/004260 dated Oct. 15, 2010.
International Search Report and Written Opinion for PCT/US2010/001952 dated Feb. 2, 2011.
International Search Report and Written Opinion for PCT/US2011/052755 dated Apr. 25, 2012.
International Search Report and Written Opinion for PCT/US2012/042738, dated Oct. 18, 2012.
International Search Report and Written Opinion for PCT/US2013/062929, dated Jan. 30, 2014.
International search report dated Nov. 30, 2009 for PCT Application No. US2009/02225.
International search report dated May 18, 2005 for PCT Application No. US2004/38403.
Invitation to Pay Additional Fees for PCT/US2009/004260 dated Mar. 19, 2010.
Invitation to Pay Additional Fees for PCT/US2010/001952 dated Oct. 29, 2010.
Invitation to Pay Additional Fees for PCT/US2011/052755 dated Feb. 16, 2012.
Invitation to Pay Additional Fees for PCT/US2013/062004, dated Jan. 2, 2014.
Jackson et al. General approach to the synthesis of short alpha-helical peptides. JACS. 1991;113:9391-9392.
Jamieson et al., Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. Aug. 12, 2004;351(7):657-67.
Jensen et al., Activation of the insulin receptor (IR) by insulin and a synthetic peptide has different effects on gene expression in IR-transfected L6 myoblasts. Biochem J. Jun. 15, 2008 ;412(3):435-45. doi: 10.1042/BJ20080279.
Ji, et al. In vivo activation of the p53 tumor suppressor pathway by an engineered cyclotide. J Am Chem Soc. Aug. 7, 2013;135(31):11623-33. doi: 10.1021/ja405108p. Epub Jul. 25, 2013.
Jordan et al., Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/beta-catenin synergy. Proc Natl Acad Sci U S A. Sep. 16, 2003;100(19):10866-71. Epub Aug. 29, 2003.
Junutula et al., Molecular characterization of Rabll interactions with members of the family of Rabl I-interacting proteins. J Biol Chem. Aug. 6, 2004;279(32):33430-7. Epub Jun. 1, 2004.
Kallen, et al. Crystal structures of human MdmX(HdmX) in complex with p53 peptide analogues reveal surprising conformational changes. Journal of Biological Chemistry. Mar. 27, 2009; 284:8812-8821.
Karle, et al. Structural charateristics of alpha-helical peptide molecules containing Aib residues. Biochemistry. Jul. 24, 1990;29(29):6747-56.
Karle. Flexibility in peptide molecules and restraints imposed by hydrogen bonds, the Aib residue, and core inserts. Biopolymers. 1996;40(1):157-80.
Karwoski et al., Lysinonorleucine cross-link formation in alpha amino heptenoic acid-substituted peptide derivatives. Biopolymers. 1978;17(5):1119-27.
Katoh et al., Cross-talk of WNT and FGF signaling pathways at GSK3beta to regulate beta-catenin and SNAIL signaling cascades. Cancer Biol Ther. Sep. 2006;5(9):1059-64. Epub Sep. 4, 2006.
Katsu et al., the human frizzled-3 (FZD3) gene on chromosome 8p21, a receptor gene for Wnt ligands, is associated with the susceptibility to schizophrenia. Neurosci Lett. 2003 Dec 15;353(1):53-6.
Kaul & Balaram, “Stereochemical Control of Peptide Folding,” Bioorg. Med. Chem. 7:105-117 (1999).
Kawamoto, Targeting the BCL9/B9L binding interaction with beta-catenin as a potential anticancer strategy. PhD Thesis. Jun. 3, 2010. Available at http://deepblue.lib.umich.edu/handle/2027.42/75846 last accessed Apr. 9, 2012. Abstract only. 2 pages.
Kazmaier, Sythesis of Quaternary Amino Acids Containing 13, y- as well as 7,6-Unsaturated Side Chains via Chelate-Enolate Claisen Rearrangement. Tetrahedron Letters. 1996;37(30):5351-4.
Kelly-Welch et al, Interleukin-4 and Interleukin-13 Signaling Connections Maps. Science. 2003;300:1527-28.
Kelso et al., “A Cyclic Metallopeptide Induces a Helicity in Short Peptide Fragments of Thermolysin,” Angew. Chem. Int. Ed. 42(4):421-424 (2003).
Kelso et al., “α-Turn Mimetics: Short Peptide α-Helices Composed of Cyclic Metallopentapeptide Modules,” J. Am. Chem. Soc. 126:4828-4842 (2004).
Kemp et al., “Studies of N-Terminal Templates for α-Helix Formation. Synthesis and Conformational Analysis of (2S,5S,8S,11S)-1-Acetyl-1,4-diaza-3-keto-5-carboxy-10-thiatricyclo[2.8.1.04,8]-tridecane (Ac-Hel1-OH),” J. Org. Chem. 56:6672-6682 (1991).
Kent. Advanced Biology. Oxford University Press. 2000.
Khalil et al., An efficient and high yield method for the N-tert-butoxycarbonyl protection of sterically hindered amino acids. Tetrahedron Lett. 1996;37(20):3441-44.
Kilby et al., “Potent Suppression of HIV-1 Replication in Humans by T-20, a Peptide Inhibitor of gp41-Mediated Virus Entry,” Nat. Med. 4(11):1302-1307 (1998).
Kim et al., Introduction of all-hydrocarbon i,i+3 staples into alpha-helices via ring-closing olefin metathesis. Org Lett. Jul. 2, 2010;12(13):3046-9. doi: 10.1021/011010449.
Kim et al., Stereochemical effects of all-hydrocarbon tethers in i,i+4 stapled peptides. Bioorg Med Chem Lett. May 1, 2009;19(9):2533-6. Epub Mar. 13, 2009.
Kim et al., Synthesis of all-hydrocarbon stapled a-helical peptides by ring-closing olefin metathesis. Nat Protoc. Jun. 2011;6(6):761-71. doi: 10.1038/nprot.2011.324. Epub May 12, 2011.
Kimmerlin et al., ‘100 years of peptide synthesis’: ligation methods for peptide and protein synthesis with applications to beta-peptide assemblies. J Pept Res. Feb. 2005;65(2):229-60.
Kinzler et al., Identification of FAP locus genes from chromosome 5q21. Science. Aug. 9, 1991;253(5020):661-5.
Kinzler et al., Lessons from hereditary colorectal cancer. Cell. Oct. 18, 1996;87(2):159-70.
Knackmuss et al., Specific inhibition of interleukin-13 activity by a recombinant human single-chain immunoglobulin domain directed against the IL-13 receptor alphal chain. Biol Chem. Mar. 2007;388(3):325-30.
Kohler et al., DNA specificity enhanced by sequential binding of protein monomers. Proc Natl Acad Sci U S A. Oct. 12, 1999;96(21):11735-9.
Kolb et al., Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angew Chem Int Ed Engl. Jun. 1, 2001;40(11):2004-2021.
Kondo et al., Frizzled 4 gene (FZD4) mutations in patients with familial exudative vitreoretinopathy with variable expressivity. Br J Ophthalmol. Oct. 2003;87(10):1291-5.
Korcsmaros et al., Uniformly curated signaling pathways reveal tissue-specific cross-talks and support drug target discovery. Bioinformatics. Aug.15, 2010;26(16):2042-50. Epub Jun. 11, 2010.
Korinek et al., Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet. Aug. 1998;19(4):379-83.
Kotha et al., Modification of constrained peptides by ring-closing metathesis reaction. Bioorg Med Chem Lett. Jun. 4, 2001;11(11):1421-3.
Kouzarides, Acetylation: a regulatory modification to rival phosphorylation? EMBO J. Mar. 15, 2000;19(6):1176-9.
Kozlovsky et aL, GSK-3 and the neurodevelopmental hypothesis of schizophrenia. Eur Neuropsychopharmacol. Feb. 2002;12(1):13-25.
Kristensen et al., Expression and characterization of a 70-kDa fragment of the insulin receptor that binds insulin. Minimizing ligand binding domain of the insulin receptor. J Biol Chem. Jul. 10, 1998;273(28):17780-6.
Kristensen et al., Functional reconstitution of insulin receptor binding site from non-binding receptor fragments. J Biol Chem. May 24, 2002;277(21):18340-5. Epub Mar. 18, 2002.
Kritzer et al., “Helical β-Peptide Inhibitors of the p53-hDM2 Interaction,” J. Am. Chem. Soc. 126:9468-9469 (2004).
Kurose et al., Cross-linking of a B25 azidophenylalanine insulin derivative to the carboxyl-terminal region of the alpha-subunit of the insulin receptor. Identification of a new insulin-binding domain in the insulin receptor. J Biol Chem. Nov. 18, 1994;269(46):29190-7.
Kussie et al, “Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain,” Science 274:948-953 (1996).
Kutchukian et al., All-atom model for stabilization of alpha-helical structure in peptides by hydrocarbon staples. J Am Chem Soc. Apr. 8, 2009;131(13):4622-7.
Kutzki et al., “Development of a Potent Bcl-xL Antagonist Based on α-Helix Mimicry,” J. Am. Chem. Soc. 124:11838-11839 (2002).
Kwon, et al. Quantitative comparison of the relative cell permeability of cyclic and linear peptides. Chem Biol. Jun. 2007;14(6):671-7.
Lacombe et al. Reduction of olefins on solid support using diimide. Tetrahedron Letters. 1998;39:6785-6786.
Lammi et al., Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet. May 2004;74(5):1043-50. Mar. 23, Epub 2004.
Laporte et al., Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system. Cell. Jan. 25, 2008;132(2):259-72.
Larock, R.C. Comprehensive Organic Transformations, New York: VCH Publishers; 1989.
Le Geuzennec et al., Molecular characterization of Sin3 PAH-domain interactor specificity and identification of PAH partners. Nucleic Acids Res. 2006;34(14):3929-37. Epub Aug. 12, 2006.
Le Geuzennec et al., Molecular determinants of the interaction of Mad with the PAH2 domain of mSin3. J Biol Chem. Jun. 11, 2004;279(24):25823-9. Epub Mar. 26, 2004.
Leduc et al., Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions. Proc Natl Acad Sci USA. 2003;100(20):11273-78.
Lee, et al. A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation. J Cell Biol. Jan. 28, 2008;180(2):341-355.
Li; et al., “A versatile platform to analyze low-affinity and transient protein-protein interactions in living cells in real time.”, 2014, 9(5):, 1946-58.
Li, et al. Systematic mutational analysis of peptide inhibition of the p53-MDM2/MDMX interactions. J Mol Biol. Apr. 30, 2010;398(2):200-13. doi: 10.1016/j.jmb.2010.03.005. Epub Mar. 10, 2010.
Liang et al., Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue. Cancer Cell. Nov. 2003;4(5):349-60.
Liskamp, et al. Conformationally restricted amino acids and dipeptides, (non)peptidomimetics and secondary structure mimetics. Recl Travl Chim Pays-Bas. 1994; 113:1-19.
Litowski & Hodges, “Designing Heterodimeric Two-stranded α-Helical Coiled-coils: Effects of Hydrophobicity and α-Helical Propensity on Protein Folding, Stability, and Specificity,” J. Biol. Chem. 277(40):37272-37279 (2002).
Little et aL, a Mutation in the LDL Receptor-Related Protein 5 Gene Results in the Autosomal Dominant High-Bone-Mass Trait. Am J Hum Genet. 2002;70:11-19.
Liu et al., Chemical Ligation Approach to Form a Peptide Bond between Unprotected Peptide Segments. Concept and Model Study. J Am Chem Soc. 1994;116(10):4149-53.
Liu et al., Targeted degradation of beta-catenin by chimeric F-box fusion proteins. Biochem Biophys Res Commun. Jan. 23, 2004;313(4):1023-9.
Lo et al., Phosphorylation by the beta-catenin/MAPK complex promotes 14-3-3-mediated nuclear export of TCF/POP-1 in signal-responsive cells in C. elegans. Cell. Apr. 2, 2004;117(1):95-106.
Logan et al., The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781-810.
Losey et al., Crystal structure of Staphylococcus aureus tRNA adenosine deaminase TadA in complex with RNA. Nat Struct Mol Biol. Feb. 2006;13(2):153-9. Epub Jan. 15, 2006.
Lou et al., The first three domains of the insulin receptor differ structurally from the insulin-like growth factor 1 receptor in the regions governing ligand specificity. Proc Natl Acad Sci U S A. Aug. 15, 2006;103(33):12429-34. Epub Aug. 7, 2006.
Loughlin et al., Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females. Proc Natl Acad Sci U S A. Jun. 29, 2004;101(26):9757-62. Epub Jun. 21, 2004.
Lu, et al. Proteomimetic libraries: design, synthesis, and evaluation of p53-MDM2 interaction inhibitors. J Comb Chem. May-Jun. 2006;8(3):315-25.
Luo, et al. Mechanism of helix induction by trifluoroethanol: a framework for extrapolating the helix-forming properties of peptides from trifluoroethanol/water mixtures back to water. Biochemistry. Jul. 8, 1997;36(27):8413-21.
Luo, et al. Wnt signaling and hunian diseases: what are the therapeutic implications? Lab Invest. Feb. 2007;87(2):97-103. Epub Jan. 8, 2007.
Luscher et al., The basic region/helix-loop-helix/leucine zipper domain of Myc proto-oncoproteins: function and regulation. Oncogene. May 13, 1999;18(19):2955-66.
Luu et al, Wnt/beta-catenin signaling pathway as a novel cancer drug target. Curr Cancer Drug Targets. Dec. 2004;4(8):653-71.
Lyu, et al. Capping Interactions in Isolated a Helices: Position-dependent Substitution Effects and Structure of a Serine-capped Peptide Helix. Biochemistry. 1993; 32:421-425.
Lyu et al, “α-Helix Stabilization by Natural and Unnatural Amino Acids with Alkyl Side Chains,” Proc. Nat'l Acad. Sci. USA 88:5317-5320 (1991).
MacMillan, Evolving strategies for protein synthesis converge on native chemical ligation. Angew Chem Int Ed Engl. Nov. 27, 2006;45(46):7668-72.
Mai, et al. A proapoptotic peptide for the treatment of solid tumors. Cancer Research. 2001; 61:7709-7712.
Mannhold, R., Kubinyi, H., Folkers, G., series eds. Molecular Drug Properties: Measurement and Prediction (Methods and Principles in Medicinal Chemistry). Wiley-VCH; 2007.
Marshall et al., Back to the future: ribonuclease A. Biopolymers. 2008;90(3):259-77.
McGahon, et al. The end of the (cell) line: methods for the study of apoptosis in vitro. Methods Cell Biol. 1995;46:153-85.
McKern et al., Structure of the insulin receptor ectodomain reveals a folded-over conformation. Nature. Sep. 14, 2006;443(7108):218-21. Epub Sep. 6, 2006.
McNamara et al. Peptides constrained by an aliphatic linkage between two C(alpha) sites: design, synthesis, and unexpected conformational properties of an i,(i + 4)-linked peptide. J Org Chem. Jun. 29, 2001;66(13):4585-95.
Menting et al., A thermodynamic study of ligand binding to the first three domains of the human insulin receptor: relationship between the receptor alpha-chain C-terminal peptide and the site 1 insulin mimetic peptides. Biochemistry. Jun. 16, 2009;48(23):5492-500. doi: 10.1021/bi900261q.
Meyers et al., Formation of mutually exclusive Rabll complexes with members of the family of Rabll-interacting proteins regulates Rabll endocytic targeting and function. J Biol Chem. Dec. 13, 2002;277(50):49003-10. Epub Oct. 9, 2002.
Miller et al., Application of Ring-Closing Metathesis to the Synthesis of Rigidified Amino Acids and Peptides. J Am Chem Soc. 1996;118(40):9606-9614.
Miller et al., Synthesis of Conformationally Restricted Amino Acids and Peptides Employing Olefin Metathesis. J Am Chem Soc. 1995;117(21):5855-5856.
Miloux et al., Cloning of the human IL-13R alphal chain and reconstitution with the IL4R alpha of a functional IL-4/IL-13 receptor complex. FEBS Lett. Jan. 20, 1997;401(2-3):163-6.
Miyaoka et al., Increased expression of Wnt-1 in schizophrenic brains. Schizophr Res. Jul. 27, 1999;38(1):1-6.
Moellering et al., Direct inhibition of the NOTCH transcription factor complex. Nature. Nov. 12, 2009;462(7270):182-8. Erratum in: Nature. Jan. 21, 2010;463(7279):384.
Moon et al., WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet. Sep. 2004;5(9):689-701.
Morin, beta-catenin signaling and cancer. Bioessays. Dec. 1999;21(12):1021-30.
Mosberg, et al. Dithioeter-containing cyclic peptides. J. Am. Chem. Soc. 1985;107(10):2986-2987.
Moy et al., Solution structure of human IL-13 and implication for receptor binding. J Mol Biol. Jun. 29, 2001;310(1):219-30.
Muchmore, et al. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature. May 23, 1996;381(6580):335-41.
Mudher et al., Alzheimer's disease-do tauists and baptists finally shake hands? Trends Neurosci. Jan. 2002;25(1):22-6.
Muir et al., Expressed protein ligation: a general method for protein engineering. Proc Natl Acad Sci U S A. Jun. 9, 1998;95(12):6705-10.
Muir, Semisynthesis of proteins by expressed protein ligation. Annu Rev Biochem. 2003;72:249-89. Epub Feb. 27, 2003.
Muppidi et al., Conjugation of spermine enhances cellular uptake of the stapled peptide-based inhibitors of p53-Mdm2 interaction. Bioorg Med Chem Lett. Dec. 15, 2011;21(24):7412-5. doi: 10.1016/j.bmc1.2011.10.009. Epub Oct. 12, 2011.
Mustapa, et al. Synthesis of a Cyclic Peptide Containing Norlanthionine: Effect of the Thioether Bridge on Peptide Conformation. J. Org. Chem. 2003;68(21):8193-8198.
Mynarcik et al., Alanine-scanning mutagenesis of a C-terminal ligand binding domain of the insulin receptor alpha subunit. J Biol Chem. Feb. 2, 1996;271(5):2439-42.
Mynarcik et al., Identification of common ligand binding determinants of the insulin and insulin-like growth factor 1 receptors. Insights into mechanisms of ligand binding. J Biol Chem. Jul. 25, 1997;272(30):18650-5.
Myung et al., The ubiquitin-proteasome pathway and proteasome inhibitors. Med Res Rev. Jul. 2001;21(4):245-73.
Nair et al., X-ray structures of Myc-Max and Mad-Max recognizing DNA. Molecular bases of regulation by proto-oncogenic transcription factors. Cell. Jan. 24, 2003;112(2):193-205.
Nakashima et al., Cross-talk between Wnt and bone morphogenetic protein 2 (BMP-2) signaling in differentiation pathway of C2C12 myoblasts. J Biol Chem. Nov. 11, 2005;280(45):37660-8. Epub Sep. 2, 2005.
Nelson & Kallenbach, “Persistence of the α-Helix Stop Signal in the S-Peptide in Trifluoroethanol Solutions,” Biochemistry 28:5256-5261 (1989).
Ngo et al. Computational complexity, protein structure prediction, and the levinthal paradox. In: The Protein Folding Problem and Tertiary Structure Prediction. K. Merz, Jr., et al. Eds. 1994:433-506.
Niemann et al., Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family. Am J Hum Genet. Mar. 2004;74(3):558-63. Epub Feb. 5, 2004.
Nilsson et al., Staudinger ligation: a peptide from a thioester and azide. Org Lett. Jun. 29, 2000;2(13):1939-41.
Nishisho et al., Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science. Aug. 9, 1991;253(5020):665-9.
Node et al., Hard Acid and Soft Nucleophile Systems. 3. Dealkylation of Esters with Aluminum Halide-Thiol and Aluminum Halide-Sulfide Stustems. J Org Chem. 1981;46:1991-93.
Notice of allowance dated Jun. 12, 2014 for U.S. Appl. No. 12/525,123.
Notice of allowance dated Jul. 18, 2016 for U.S. Appl. No. 14/498,063.
Notice of allowance dated Jul. 28, 2016 for U.S. Appl. No. 14/498,063.
Notice of allowance dated Aug. 1, 2014 for U.S. Appl. No. 13/767,852.
Notice of allowance dated Aug. 6, 2012 for U.S. Appl. No. 12/796,212.
Notice of allowance dated Oct. 23, 2015 for U.S. Appl. No. 13/252,751.
Notice of allowance dated Nov. 6, 2014 for U.S. Appl. No. 13/767,857.
Office action dated Jan. 3, 2013 for U.S. Appl. No. 12/593,384.
Office action dated Jan. 13, 2014 for U.S. Appl. No. 13/767,857.
Office action dated Jan. 17, 2014 for U.S. Appl. No. 13/816,880.
Office action dated Jan. 26, 2009 for U.S. Appl. No. 11/148,976.
Office Action dated Jan. 30, 2008 for U.S. Appl. No. 10/981,873.
Office action dated Feb. 6, 2014 for U.S. Appl. No. 13/680,905.
Office action dated Feb. 9, 2012 for U.S. Appl. No. 12/420,816.
Office action dated Feb. 17, 2011 for U.S. Appl. No. 12/796,212.
Office action dated Mar. 22, 2013 for U.S. Appl. No. 12/233,555.
Office action dated Mar. 26, 2015 for U.S. Appl. No. 14/070,354.
Office action dated Apr. 9, 2014 for U.S. Appl. No. 13/767,852.
Office action dated Apr. 10, 2015 for U.S. Appl. No. 14/460,848.
Office action dated Apr. 18, 2011 for U.S. Appl. No. 12/182,673.
Office action dated Jun. 28, 2012 for U.S. Appl. No. 12/233,555.
Office action dated Jul. 15, 2013 for U.S. Appl. No. 13/570,146.
Office action dated Jul. 16, 2014 for U.S. Appl. No. 13/767,857.
Office action dated Jul. 21, 2014 for U.S. Appl. No. 13/370,057.
Office action dated Jul. 24, 2015 for U.S. Appl. No. 13/252,751.
Office action dated Aug. 6, 2015 for U.S. Appl. No. 14/498,063.
Office action dated Aug. 9, 2010 for U.S. Appl. No. 12/182,673.
Office action dated Sep. 2, 2015 for U.S. Appl. No. 14/608,641.
Office action dated Sep. 18, 2013 for U.S. Appl. No. 13/767,857.
Office action dated Sep. 23, 2013 for U.S. Appl. No. 13/680,905.
Office action dated Oct. 10, 2013 for U.S. Appl. No. 13/816,880.
Office action dated Oct. 18, 2011 for U.S. Appl. No. 12/796,212.
Office action dated Nov. 5, 2002 for U.S. Appl. No. 09/574,086.
Office action dated Nov. 25, 2009 for U.S. Appl. No. 11/148,976.
Office action dated Dec. 5, 2008 for U.S. Appl. No. 10/981,873.
Office action dated Dec. 19, 2014 for U.S. Appl. No. 14/068,844.
Office action dated Dec. 23, 2015 for U.S. Appl. No. 14/498,063.
Office action dated Dec. 29, 2011 for U.S. Appl. No. 12/233,555.
Office action dated Dec. 31, 2013 for U.S. Appl. No. 12/525,123.
Office Communication, dated Jan. 3, 2013, for U.S. Appl. No. 12/593,384.
Okamura et al., Redundant regulation of T cell differentiation and TCRalpha gene expression by the transcription factors LEF-1 and TCF-1. Immunity. Jan. 1998;8(1):11-20.
Olson et al., Sizing up the heart: development redux in disease. Genes Dev. Aug. 15, 2003;17(16):1937-56. Epub Jul. 31, 2003.
O'Neil & DeGrado, “A Thermodynamic Scale for the Helix-forming Tendencies of the Commonly Occurring Amino Acids,” Science 250:646-651(1990).
Or et al. Cysteine alkylation in unprotected peptides: synthesis of a carbavasopressin analogue by intramolecular cystein alkylation. J. Org. Chem. Apr. 1991;56(9):3146-3149.
Pakotiprapha et al., Crystal structure of Bacillus stearothermophilus UvrA provides insight into ATP-modulated dimerization, UvrB interaction, and DNA binding. Mol Cell. Jan. 18, 2008;29(1):122-33. Epub Dec. 27, 2007.
Paquette, L.A., ed. Encyclopedia of Reagents for Organic Synthesis. New York; John Wiley & Sons; 1995.
Pazgier, et al. Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX. Proc Natl Acad Sci U S A. Mar. 24, 2009;106(12):4665-70. doi: 10.1073/pnas.0900947106. Epub Mar. 2, 2009.
Pellois et al., Semisynthetic proteins in mechanistic studies: using chemistry to go where nature can't. Curr Opin Chem Biol. Oct. 2006;10(5):487-91. Epub Aug. 28, 2006.
Perantoni, Renal development: perspectives on a Wnt-dependent process. Semin Cell Dev Biol. Aug. 2003;14(4):201-8.
Peryshkov, et al. Z-Selective olefin metathesis reactions promoted by tungsten oxo alkylidene complexes. Am Chem Soc. Dec. 28, 2011;133(51):20754-7. doi: 10.1021/ja210349m. Epub Nov. 30, 2011.
Phan, et al. Structure-based design of high affinity peptides inhibiting the interaction of p53 with MDM2 and MDMX. J Biol Chem. Jan. 15, 2010;285(3):2174-83. doi: 10.1074/jbc.M109.073056. Epub Nov. 12, 2009.
Phelan, et al. A General Method for Constraining Short Peptides to an α-Helical Conformation. J. Am. Chem. Soc. 1997;119:455-460.
Picksley et al., Immunochemical analysis of the interaction of p53 with MDM2;—fine mapping of the MDM2 binding site on p53 using synthetic peptides. Oncogene. Sep. 1994;9(9):2523-9.
Pillutla et al., Peptides identify the critical hotspots involved in the biological activation of the insulin receptor. J Biol Chem. Jun. 21, 2002;277(25):22590-4. Epub Apr. 18, 2002.
Polakis, The oncogenic activation of beta-catenin. Curr Opin Genet Dev. Feb. 1999;9(1):15-21.
Qiu et al., Convenient, Large-Scale Asymmetric Synthesis of Enantiomerically Pure trans-Cinnamylglycine and -a-Alanine. Tetrahedron. 2000;56:2577-82.
Rasmussen, et al. Ruthenium-catalyzed cycloaddition of aryl azides and alkynes. Org Lett. Dec. 20, 2007;9(26):5337-9.
Rawlinson et al., CRM1-mediated nuclear export of dengue virus RNA polymerase NS5 modulates interleukin-8 induction and virus production. J Biol Chem. Jun. 5, 2009;284(23):15589-97. Epub Mar. 18, 2009.
Reya et al., Wnt signalling in stem cells and cancer. Nature. Apr. 14, 2005;434(7035):843-50.
Rich et al., Synthesis of the cytostatic cyclic tetrapeptide, chlamydocin. Tetranderon Letts. 1983;24(48):5305-08.
Roberts, et al. Efficient synthesis of thioether-based cyclic peptide libraries. Tetrahedon Letters. 1998; 39: 8357-8360.
Roberts, et al. Examination of methodology for the synthesis of cyclic thioether peptide libraries derived from linear tripeptides. J Pept Sci. Dec. 2007;13(12):811-21.
Robitaille et al., Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet. Oct. 2002;32(2):326-30. Epub Aug. 12, 2002.
Rodova et al., The polycystic kidney disease-1 promoter is a target of the beta-catenin/T-cell factor pathway. J Biol Chem. Aug. 16, 2002;277(33):29577-83. Epub Jun. 4, 2002.
Roos et al., Synthesis of a-Substituted a-Amino Acids via Cationic Intermediates. J Org Chem. 1993;58:3259-68.
Ross et aL, Inhibition of adipogenesis by Wnt signaling. Science. Aug. 11, 2000;289(5481):950-3.
Rostovtsev, et al. A stepwise huisgen cycloaddition process: copper (i)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew. Chem. Int. Ed. Engl. Jul. 15, 2002;41(14):2596-2599.
Ruan et al., “Metal Ion Enhanced Helicity in Synthetic Peptides Containing Unnatural, Metal-ligating Residues,” J. Am. Chem. Soc. 112:9403-9404 (1990).
Rudinger J, “Characteristics of the amino acids as components of a peptide hormone sequence,” Peptide Hormones, JA Parsons Edition, University Park Press, Jun. 1976, pp. 1-7.
Ruffolo and Shore. BCL-2 Selectively Interacts with the BID-Induced Open Conformer of BAK, Inhibiting BAK Auto-Oligomerization. J. Biol. Chern. 2003;278(27):25039-25045.
Sadot et al., Down-regulation of beta-catenin by activated p53. Mol Cell Biol. Oct. 2001;21(20):6768-81.
Sampietro et al., Crystal structure of a beta-catenin/BCL9/Tcf4 complex. Mol Cell. Oct. 20, 2006;24(2):293-300.
Sanchez-Garcia, et al. Tumorigenic activity of the BCR-ABL oncogenes is mediated by BCL2. Proc Natl Acad Sci U S A. Jun. 6, 1995;92(12):5287-91.
Ösapay & Taylor, “Multicyclic Polypeptide Model Compounds. 2. Synthesis and Conformational Properties of a Highly α-Helical Uncosapeptide Constrained by Three Side-chain to Side-chain Lactam Bridges,” J. Am. Chem. Soc. 114:6966-6973 (1992).
Satoh et al., AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet. Mar. 2000;24(3):245-50.
Sattler et al. Structure of Bcl-xL-Back peptide complex: recognition between regulators of apoptosis. Science. 275:983-986 (1997).
Saxon et al., Cell surface engineering by a modified Staudinger reaction. Science. Mar. 17, 2000;287(5460):2007-10.
Schaffer et al., A novel high-affinity peptide antagonist to the insulin receptor. Biochem Biophys Res Commun. Nov. 14, 2008;376(2):380-3. doi: 10.1016/j.bbrc.2008.08.151. Epub Sep. 7, 2008.
Schaffer et al., Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks. Proc Natl Acad Sci U S A. Apr. 15, 2003;100(8):4435-9. Epub Apr. 8, 2003.
Schafmeister et al. An all-hydrocarbon crosslinking system for enhancing the helicity and metabolic stability of peptides. J. Am Chem. Soc. 2000;122:5891-5892.
Scheffzek et al., The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science. Jul. 18, 1997;277(5324):333-8.
Schinzel et al., The phosphate recognition site of Escherichia coli maltodextrin phosphorylase. FEBS Lett. Jul. 29, 1991;286(1-2):125-8.
Schmiedeberg et al. Reversible backbone protection enables combinatorial solid-phase ring-closing metathesis reaction (RCM) in peptides. Org Lett. Jan. 10, 2002;4(1):59-62.
Scholtz et al., The mechanism of alpha-helix formation by peptides. Annu Rev Biophys Biomol Struct. 1992;21:95-118.
Schrock et al., Tungsten(VI) Neopentylidyne Complexes. Organometallics. 1982;1:1645-51.
Schwarzer et al., Protein semisynthesis and expressed protein ligation: chasing a protein's tail. Curr Opin Chem Biol. Dec. 2005;9(6):561-9. Epub Oct. 13, 2005.
Scorrano, et al. A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell. Jan. 2002;2(1):55-67.
Seabra et al., Rab GTPases, intracellular traffic and disease. Trends Mol Med. Jan. 2002;8(1):23-30.
Seebach, et al. Self-Regeneration of Stereocenters (SRS)—Applications, Limitations, and Abandonment of a Synthetic Principle. Angew. Chem. Int. Ed. Engl. 1996;35:2708-2748.
Shair, A closer view of an oncoprotein-tumor suppressor interaction. Chem Biol. Nov. 1997;4(11):791-4.
Shepherd et al., “Single Turn Peptide Alpha Helices with Exceptional Stability in Water,” J. Am. Chem. Soc. 127:2974-2983 (2005).
Shiba et al., Structural basis for Rabll-dependent membrane recruitment of a family of Rabll-interacting protein 3 (FIP3)/Arfophilin-1. Proc Natl Acad Sci U S A. Oct. 17, 2006;103(42):15416-21. Epub Oct. 9, 2006.
Si et aL, CCN1/Cyr61 is regulated by the canonical Wnt signal and plays an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells. Mol Cell Biol. Apr. 2006;26(8):2955-64.
Sia et al., “Short Constrained Peptides that Inhibit HIV-1 Entry,” Proc. Nat'l Acad. Sci. USA 99(23):14664-14669 (2002).
Siddle et al., Specificity in ligand binding and intracellular signalling by insulin and insulin-like growth factor receptors. Biochem Soc Trans. Aug. 2001;29(Pt 4):513-25.
Skinner et al., Basic helix-loop-helix transcription factor gene family phylogenetics and nomenclature. Differentiation. Jul. 2010;80(1):1-8. doi: 10.1016/j.diff.2010.02.003. Epub Mar. 10, 2010.
Smith et al., Structural resolution of a tandem hormone-binding element in the insulin receptor and its implications for design of peptide agonists. Proc Natl Acad Sci U S A. Apr. 13, 2010;107(15):6771-6. doi: 10.1073/pnas.1001813107. Epub Mar. 26, 2010.
Soucek et al., Modelling Myc inhibition as a cancer therapy. Nature. Oct. 2, 2008;455(7213):679-83. Epub Aug. 17, 2008.
Spierings, et al. Connected to death: the (unexpurgated) mitochondrial pathway of apoptosis. Science. 2005; 310:66-67.
Stein et al., Rab proteins and endocytic trafficking: potential targets for therapeutic intervention. Adv Drug Deliv Rev. Nov. 14, 2003;55(11):1421-37.
Stenmark et al., The Rab GTPase family. Genome Biol. 2001;2(5):3007.1-3007.7.
Stewart, et al. Cell-penetrating peptides as delivery vehicles for biology and medicine. Org Biomol Chem. Jul. 7, 2008;6(13):2242-55. doi: 10.1039/b719950c. Epub Apr. 15, 2008.
Still et al., Semianalytical Treatment of Solvation for Molecular Mechanics and Dynamics. J Am Chem Soc. 1990;112:6127-29.
STN search notes for Lu reference, 4 pages, 2006.
Stueanaes et al., Beta-adrenoceptor stimulation potentiates insulin-stimulated PKB phosphorylation in rat cardiomyocytes via cAMP and PKA. Br J Pharmacol. May 2010;160(1):116-29. doi: 10.1111/j.1476-5381.2010.00677.x.
Su et al., Eradication of pathogenic beta-catenin by Skpl/Cullin/F box ubiquitination machinery. Proc Natl Acad Sci U S A. Oct. 28, 2003;100(22):12729-34. Epub Oct. 16, 2003.
Surinya et al., Role of insulin receptor dimerization domains in ligand binding, cooperativity, and modulation by anti-receptor antibodies. J Biol Chem. May 10, 2002;277(19):16718-25. Epub Mar. 1, 2002.
Suzuki, et al. Structure of Bax: coregulation of dimer formation and intracellular localization. Cell. Nov. 10, 2000;103(4):645-54.
Szewczuk, et al. Synthesis and Biological activity of new conformationally restricted analogues of pepstatin. Int. J. Peptide Protein. Res. 1992; 40:233-242.
Takeda et al., Human sebaceous tumors harbor inactivating mutations in LEF I . Nat Med. Apr. 2006;12(4):395-7. Epub Mar. 26, 2006.
Tanaka, Design and synthesis of non-proteinogenic amino acids and secondary structures of their peptides. Yakugaku Zasshi. Oct. 2006:126(10):931-44. Japanese.
Taylor. The synthesis and study of side-chain lactam-bridged peptides. Biopolymers. 2002;66(1):49-75.
Thompson et al., Mutants of interleukin 13 with altered reactivity toward interleukin 13 receptors. J Biol Chem. Oct. 15, 1999;274(42):29944-50.
Tian et aL, the role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. Dec. 25, 2003;349(26):2483-94.
Titus, et al. Human K/natural killer cells targeted with hetero-cross-linked antibodies specifically lyse tumor cells in vitro and prevent tumor growth in vivo. J Immunol. Nov. 1, 1987;139(9):3153-8.
Tolbert et al., New methods for proteomic research: preparation of proteins with N-terminal cysteines for labeling and conjugation. Angew Chem Int Ed Engl. Jun. 17, 2002;41(12):2171-4.
Toomes et al., Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Am J Hum Genet. Apr. 2004;74(4):721-30. Epub Mar. 11, 2004.
Torrance et al., Combinatorial chemoprevention of intestinal neoplasia. Nat Med. Sep. 2000;6(9):1024-8.
Trnka & Grubbs, “The Development of L2X2Ru=CHR Olefin Metathesis Catalysts: An Organometallic Success Story,” Acc. Chem. Res. 34:18-29 (2001).
Tsuji et al., Antiproliferative activity of REIC/Dkk-3 and its significant down-regulation in non-small-cell lung carcinomas. Biochem Biophys Res Commun. Nov. 23, 2001;289(1):257-63.
Tugyi, et al. The effect of cyclization on the enzymatic degradation of herpes simplex virus glycoprotein D derived epitope peptide. J Pept Sci. Oct. 2005;11(10):642-9.
Tyndall et al. Macrocycles mimic the extended peptide conformation recognized by aspartic, serine, cysteine and metallo proteases. Curr Med Chem. Jul. 2001;8(8):893-907.
Uesugi et al., The alpha-helical FXXPhiPhi motif in p53: TAF interaction and discrimination by MDM2. Proc Natl Acad Sci U S A. Dec. 21, 1999;96(26):14801-6.
U.S. Appl. No. 14/750,649, filed Jun. 25 2015.
U.S. Appl. No. 14/864,801, filed Sep. 24, 2015.
U.S. Appl. No. 14/718,288, filed May 21, 2015.
U.S. Appl. No. 14/852,368, filed Sep. 11, 2015.
U.S. Appl. No. 14/853,894, filed Sep. 14, 2015.
U.S. Appl. No. 14/864,687, filed Sep. 24, 2015.
U.S. Appl. No. 14/866,445, filed Sep. 25, 2015.
U.S. Appl. No. 61/385,405, filed Sep. 22, 2010.
Vaickus et al., Immune markers in hematologic malignancies. Crit Rev Oncol Hematol. Dec. 1991; 11(4):267-97.
Van Genderen et al., Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice. Genes Dev. Nov. 15, 1994;8(22):2691-703.
Van Gijn et al., The wnt-frizzled cascade in cardiovascular disease. Cardiovasc Res. Jul. 2002;55(1):16-24.
Varallo et al., Beta-catenin expression in Dupuytren's disease: potential role for cell-matrix interactions in modulating beta-catenin levels in vivo and in vitro. Oncogene. Jun. 12, 2003;22(24):3680-4.
Vartak et al., Allosteric Modulation of the Dopamine Receptor by Conformationally Constrained Type VI (3-Turn Peptidomimetics of Pro-Leu-Gly-NH2. J Med Chem. 2007;50(26):6725-6729.
Venancio et al., Reconstructing the ubiquitin network: cross-talk with other systems and identification of novel functions. Genome Biol. 2009;10(3):R33. Epub Mar. 30, 2009.
Verdine et al., The challenge of drugging undruggable targets in cancer: lessons learned from targeting BCL-2 family members. Clin Cancer Res. Dec. 15, 2007;13(24):7264-70.
Verma et al., Small interfering RNAs directed against beta-catenin inhibit the in vitro and in vivo growth of colon cancer cells. Clin Cancer Res. Apr. 2003;9(4):1291-300.
Viallet, et al. Tallimustine is inactive in patients with previously treated small cell lung cancer. A phase II trial of the National Cancer Institute of Canada Clinical Trials Group. Lung Cancer. Nov. 1996;15(3):367-73.
Voet D, Voet JG, Biochemistry, Second Edition, John Wiley & Sons, Inc., 1995, pp. 235-241.
Walensky, et al. A stapled BID BH3 helix directly binds and activates BAX. Mol. Cell. Oct. 20, 2006;24(2):199-210.
Walensky, et al. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science. Sep. 3, 2004;305(5689):1466-70.
Walter et al., Critical role for IL-13 in the development of allergen-induced airway hyperreactivity. J Immunol. Oct. 15, 2001;167(8):4668-75.
Wang, 4-Alkyl-2-trichloromethyloxazolidin-5-ones: Valuable Precursors to Enantiomerically Pure C- and N-Protected a-Alkyl Prolines. Synlett. 1999;1:33-36.
Wang et al. Cell permeable Bcl-2 binding peptides: a chemical approach to apoptosis induction in tumor cells. Cancer Res. Mar. 15, 2000;60(6):1498-502.
Wang et al. Enhanced metabolic stability and protein-binding properties of artificial alpha helices derived from a hydrogen-bond surrogate: application to Bcl-xL. Angew Chem Int Ed Engl. Oct. 14, 2005;44(40):6525-9.
Wang, et al. Evaluation of biologically relevant short alpha-helices stabilized by a main-chain hydrogen-bond surrogate. J Am Chem Soc. Jul. 19, 2006;128(28):9248-56.
Wang et al., Inhibition of p53 degradation by Mdm2 acetylation. FEBS Lett. Mar. 12, 2004;561(1-3):195-201.
Wang, et al. Nucleation and stability of hydrogen-bond surrogate-based alpha-helices. Org Biomol Chem. Nov. 21, 2006;4(22):4074-81.
Wei et al., Disorder and structure in the Rabll binding domain of Rabll family interacting protein 2. Biochemistry. Jan. 27, 2009;48(3):549-57. doi: 10.1021/bi8020197.
Wei, et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev. Aug. 15, 2000;14(16):2060-71.
Wild et al., “Peptides Corresponding to a Predictive α-Helical Domain of Human Immunodeficiency Virus Type 1 gp4l are Potent Inhibitors of Virus Infection,” Proc. Nat'l Acad. Sci. USA 91:9770-9774 (1994).
Wilen et al., Strategies in Optical Resolution. Tetrahedron. 1977;33:2725-36.
Wilen, Tables of Resolving Agents and Optical Resolutions. E.L. Eliel, ed. Universtify of Notre Dame Press, Notre Dame, IN. 1972:268-98.
Williams and Im. Asymmetric Synthesis of Nonsubstituted and α,α-Disubstituted α-Amino Acids via Disatereoselective Glycine Enolate Alkylations. JACS. 1991;113:9276-9286.
Wills-Karp et al., Interleukin-13: central mediator of allergic asthma. Science. Dec. 18, 1998;282(5397):2258-61.
Wills-Karp, Interleukin-13 in asthma pathogenesis. Immunol Rev. Dec. 2004;202:175-90.
Wills-Karp, the gene encoding interleukin-13: a susceptibility locus for asthma and related traits. Respir Res. 2000;1(1):19-23. Epub Jul. 17, 2000.
Wilson et al., The FIP3-Rabll protein complex regulates recycling endosome targeting to the cleavage furrow during late cytokinesis. Mol Biol Cell. Feb. 2005;16(2):849-60. Epub Dec. 15, 2004.
Woon et al., Linking of 2-oxoglutarate and substrate binding sites enables potent and highly selective inhibition of JmjC histone demethylases. Angew Chem Int Ed Engl. Feb. 13, 2012;51(7):1631-4. doi: 10.1002/anie.201107833. Epub Jan. 12, 2012.
Wu, et al. Regiospecific Synthesis of 1,4,5-Trisubstituted-1,2,3-triazole via One-Pot Reaction Promoted by Copper(I) Salt. Synthesis. 2005(8): 1314-1318.
Xi et al., Use of DNA and peptide nucleic acid molecular beacons for detection and quantification of rRNA in solution and in whole cells. Appl Environ Microbiol. Sep. 2003;69(9):5673-8.
Xing, et al. Crystal structure of a beta-catenin/axin complex suggests a mechanism for the beta¬catenin destruction complex. Genes Dev. Nov. 15, 2003;17(22):2753-64. Epub Nov. 4, 2003.
Yang et al. Synthesis and helical structure of lactam bridged BH3 peptides derived from pro-apoptotic Bcl-2 family proteins. Bioorg Med Chem Lett. Mar. 22, 2004;14(6):1403-6.
Yang et al., Therapeutic dosing with anti-interleukin-13 monoclonal antibody inhibits asthma progression in mice. J Pharmacol Exp Ther. Apr. 2005;313(1):8-15. Epub Jan. 11, 2005.
Yu et al., The role of Axin2 in calvarial morphogenesis and craniosynostosis. Development. Apr. 2005; 132(8): 1995-2005.
Zamzami et al. The thiol crosslinking agent diamide overcomes the apoptosis-inhibitory effect of Bcl-2 by enforcing mitochondrial permeability transition. Oncogene. Feb. 26, 1998;16(8):1055-63.
Zhang, et al. 310 Helix versus alpha-helix: a molecular dynamics study of conformational preferences of Aib and Alanine. J. American Cancer Society. Dec. 1994; 116(26):11915-11921.
Zhou, et al. Identification of ubiquitin target proteins using cell-based arrays. J Proteome Res. 2007; 6:4397-4406.
Zhou et al., Lymphoid enhancer factor 1 directs hair follicle patterning and epithelial cell fate. Genes Dev. Mar. 15, 1995;9(6):700-13.
Zhou et aL, Tyrosine kinase inhibitor STI-571/Gleevec down-regulates the beta-catenin signaling activity. Cancer Lett. Apr. 25, 2003;193(2):161-70.
Zimm & Bragg, “Theory of the Phase Transition between Helix and Random Coil in Polypeptide Chains,” J. Chem. Phys. 31(2):526-535 (1959).
Zor et aL, Solution structure of the KIX domain of CBP bound to the transactivation domain of c-Myb. J Mol Biol. Mar. 26, 2004;337(3):521-34.
Adams, et al. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. Feb. 26, 2007; 26(9): 1324-1337.
Adamski, et al. The cellular adaptations to hypoxia as novel therapeutic targets in childhood cancer. Cancer Treat Rev. May 2008;34(3):231-46. doi: 10.1016/j.ctrv.2007.11.005. Epub Jan. 18, 2008.
Aki, et al. Competitive Binding of Drugs to the Multiple binding Sites on Human Serum Albumin. A Calorimetric Study. J Thermal Anal. Calorim. 57:361-70 (1999).
Armstrong, et al. Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification. Cancer Cell. Feb. 2003;3(2):173-83.
Bhattacharya, et al. Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev. Jan. 1, 1999;13(1):64-75.
Braun, et al. Photoreactive stapled BH3 peptides to dissect the BCL-2 family interactome. Chem Biol. Dec. 22, 2010;17(12):1325-33. doi: 10.1016/j.chembio1.2010.09.015.
Caramelo, et al. [Response to hypoxia. A systemic mechanism based on the control of gene expression]. Medicina (B Aires). 2006;66(2):155-64 (in French with English abstract).
Chang et al., Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis.Mol. Cell., 26(5):745-752, 2007.
Checco, et al. α/β3-Peptide foldamers targeting intracellular protein—protein interactions with activity in living cells. Journal of the American Chemical Society 137.35 (2015): 11365-11375.
Chen, et al. Dual inhibition of PI3K and mTOR mitigates compensatory AKT activation and improves tamoxifen response in breast cancer. Mol Cancer Res. Oct. 2013;11(10):1269-78. doi: 10.1158/1541-7786.MCR-13/0212. Epub Jun. 27, 2013.
Chervenak, et al. Calorimetric analysis of the binding of lectins with overlapping carbohydrate-binding ligand specificities. Biochemistry. Apr. 25, 1995;34(16):5685-95.
Chou, et al., “Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors,” Lab of Pharma, John Hopkins 22: 27-55 (1984).
Co-pending U.S. Appl. No. 15/956,333, filed Apr. 18, 2018.
Co-pending U.S. Appl. No. 15/794,355, filed Oct. 26, 2017.
Co-pending U.S. Appl. No. 15/917,054, filed Mar. 9, 2018.
Co-pending U.S. Appl. No. 15/917,560, filed Mar. 9, 2018.
Co-pending U.S. Appl. No. 15/975,298, filed May 9, 2018.
Co-pending U.S. Appl. No. 15/982,700, filed May 17, 2018.
Co-pending U.S. Appl. No. 16/002,977, filed Jun. 7, 2018.
Co-pending U.S. Appl. No. 16/009,755, filed Jun. 15, 2018.
Corbell, et al. A comparison of biological and calorimetric analyses of multivalent glycodendrimer ligands for concanavalin A. Tetrahedron: Asymmetry, vol. 11, Issue 1, Jan. 28, 2000, pp. 95-111.
Crook, et al. Degradation of p53 can be targeted by HPV E6 sequences distinct from those required for p53 binding and trans-activation. Cell. Nov. 1, 1991;67(3):547-56.
De; Guzman et al., “Interaction of the TAZ1 Domain of CREB-Binding Protein with the Activation Domain of CITED2. J Biological Chemistry, vol. 279, pp. 3042-3049, Jan. 23, 2004.”
Ding, et al. Retinal disease in mice lacking hypoxia-inducible transcription factor-2alpha. Invest Ophthalmol Vis Sci. Mar. 2005;46(3):1010-6.
Eul, et al. Impact of HIF-1alpha and HIF-2alpha on proliferation and migration of human pulmonary artery fibroblasts in hypoxia. FASEB J. Jan. 2006;20(1):163-5. Epub Nov. 1, 2005.
European search report and search opinion dated Oct. 6, 2015 for EP Application No. 15153712-3.
Fields, G. B. Chapter 3: Principles and Practice of Solid-Phase Peptide Synthesis. Synthetic Peptides: A User's Guide, GA Grant Edition, (1992), pp. 77-183.
Forooghian, et al. Anti-angiogenic effects of ribonucleic acid interference targeting vascular endothelial growth factor and hypoxia-inducible factor-1alpha. Am J Ophthalmol. Nov. 2007;144(5):761-8. Epub Sep. 17, 2007.
Freedman, et al. Structural basis for negative regulation of hypoxia-inducible factor-1alpha by CITED2. Nat Struct Biol. Jul. 2003;10(7):504-12.
Galanis, et al. Reactive oxygen species and HIF-1 signalling in cancer. Cancer Lett. Jul. 18, 2008;266(1):12-20. doi: 10.1016/j.canlet.2008.02.028. Epub Apr. 18, 2008.
Goudreau, et al. Potent inhibitors of the hepatitis C virus NS3 protease: design and synthesis of macrocyclic substrate-based β3-strand mimics. The Journal of organic chemistry 69.19 (2004): 6185-6201.
Graziano, et al. Linkage of proton binding to the thermal unfolding of Sso7d from the hyperthermophilic archaebacterium Sulfolobus solfataricus. Int J Biol Macromol. Oct. 1999;26(1):45-53.
Greenaway, J., et al. ABT-510 induces tumor cell apoptosis and inhibits ovarian tumor growth in an orthotopic, syngeneic model of epithelial ovarian cancer. Mol. Cancer Ther. Jan. 8, 2009:64-74.
Guan, J., et al. The xc-cystine/glutamate antiporter as a potential therapeutic target for small-cell lung cancer: use of sulfasalazine. Cancer Chemother. Pharmacol. Aug. 2009;64(3):463-72. Epub. Dec. 24, 2008.
Hein, et al. Copper(I)-catalyzed cycloaddition of organic azides and 1-iodoalkynes. Angew Chem Int Ed Engl. 2009;48(43):8018-21. doi: 10.1002/anie.200903558.
Hermeking. MicroRNAs in the p53 network: micromanagement of tumour suppression. Nat Rev Cancer. Sep. 2012;12(9):613-26. doi: 10.1038/nrc3318. Epub Aug. 17, 2012.
Hermeking, “p53 enters the microRNA world,” Cancer Cell, 12(5):414-418, 2007.
Hutcheson, et al. Fulvestrant-induced expression of ErbB3 and ErbB4 receptors sensitizes oestrogen receptor-positive breast cancer cells to heregulin β1. Breast Cancer Res. 13 (2) (2011) doi: 10.1186/bcr2848.
Inoue, et al. Expression of hypoxia-inducible factor 1 alpha and 2alpha in choroidal neovascular membranes associated with age-related macular degeneration. Br J Ophthalmol. Dec. 2007;91(12):1720-1.
“International search report and written opinion dated Oct. 3, 2014 for PCT Application No. 2014/021292.”
International search report and written opinion dated Dec. 1, 2015 for PCT Application No. US2015/049458.
International search report and written opinion dated Dec. 19, 2016 for PCT Application No. PCT/US2016/050789.
International search report dated Oct. 22, 2009 for PCT Application No. US2009/00837.
Jenkins, D.E., et al. In Vivo Monitoring of Tumor Relapse and Metastasis using Bioluminescent PC-3M-luc-C6 cells in Murine Models of Human Prostate Cancer. Clin. Exp. Metastasis. 2003;20(8):745-56.
Jenkins, et al. Bioluminescent imaging (BLI) to improve and refine traditional murine models of tumor growth and metastasis. Clin Exp Metastasis. 2003; 20(8): 733-44.
Joseph, et al. Stapled BH3 peptides against MCL-1: mechanism and design using atomistic simulations. PloS one 7.8 (2012): e43985.
Kelekar, et al. Bcl-2-family proteins: the role of the BH3 domain in apoptosis. Trends Cell Biol. Aug. 1998;8(8):324-30.
Lau, et al. Investigating peptide sequence variations for ‘double-click’ stapled p53 peptides. Org Biomol Chem. Jun. 28, 2014;12(24):4074-7.
Le, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. Jun. 25, 2015;372(26):2509-20. doi: 10.1056/NEJMoa1500596. Epub May 30, 2015.
Lelekakis, M., et al. A novel orthotopic model of breast cancer metastasis to bone. Clin. Exp. Metastasis. Mar. 1999;17(2):163-70.
Leshchiner, et al. Direct activation of full-length proapoptotic BAK. PNAS, Mar. 12, 2013, vol. 110, No. 11, E986-E995.
Lessene, et al. BCL-2 family antagonists for cancer therapy. Nature reviews Drug discovery 7.12 (2008): 989-1000.
Li, et al. A convenient preparation of 5-iodo-1,4-disubstituted-1,2,3-triazole: multicomponent one-pot reaction of azide and alkyne mediated by CUL-NBS. J Org Chem. May 2, 2008;73(9):3630-3. doi: 10.1021/jo800035v. Epub Mar. 22, 2008.
Marignol, et al. Hypoxia in prostate cancer: a powerful shield against tumour destruction? Cancer Treat Rev. Jun. 2008;34(4):313-27. doi: 10.1016/j.ctrv.2008.01.006. Epub Mar. 10, 2008.
Mosberg, et al. Dithioether-containing cyclic peptides. Journal of the American Chemical Society. 1985;107(10):2986-2987.
Mott, et al. Piercing the armor of hepatobiliary cancer: Bcl-2 homology domain 3 (BH3) mimetics and cell death. Hepatology 46.3 (2007): 906-911.
Nahi, et al. Mutated and non-mutated TP53 as targets in the treatment of leukaemia. Br J Haematol. 2008 May;141(4):445-53.
Notice of allowance dated Mar. 30, 2015 for U.S. Appl. No. 13/655,378.
Notice of allowance dated May 13, 2014 for U.S. Appl. No. 13/352,223.
Notice of allowance dated Nov. 17, 2016 for U.S. Appl. No. 14/070,306.
Notice of allowance dated Dec. 12, 2017 for U.S. Appl. No. 15/287,513.
O'Donnell, et al. Acute Myeloid Leukemia, Version 2.2013: Featured Updates to the NCCN Guidelines. Journal of the National Comprehensive Cancer Network : JNCCN. 2013;11(9):1047-1055.
Office action dated Jan. 12, 2017 for U.S. Appl. No. 15/278,824.
Office action dated Jan. 17, 2018 for U.S. Appl. No. 14/608,641.
Office Action dated Mar. 28, 2016 for U.S. Appl. No. 14/070,306.
Office Action dated Jun. 4, 2015 for U.S. Appl. No. 14/070,306.
Office action dated Jun. 26, 2012 for U.S. Appl. No. 12/378,047.
Office action dated Jul. 7, 2017 for U.S. Appl. No. 14/864,801.
Office action dated Aug. 14, 2012 for U.S. Appl. No. 13/352,223.
Office action dated Aug. 22, 2011 for U.S. Appl. No. 12/378,047.
Office action dated Aug. 30, 2017 for U.S. Appl. No. 15/287,513.
Office action dated Sep. 5, 2017 for U.S. Appl. No. 15/093,869.
Office action dated Sep. 7, 2017 for U.S. Appl. No. 15/093,426.
Office action dated Sep. 16, 2016 for U.S. Appl. No. 14/325,933.
Office action dated Oct. 26, 2017 for U.S. Appl. No. 14/460,848.
Office action dated Nov. 15, 2017 for U.S. Appl. No. 15/240,505.
Office action dated Nov. 24, 2017 for U.S. Appl. No. 15/135,098.
Office action dated Dec. 19, 2012 for U.S. Appl. No. 13/352,223.
Palani, et al. Histone deacetylase inhibitors enhance the anticancer activity of nutlin-3 and induce p53 hyperacetylation and downregulation of MDM2 and MDM4 gene expression. Invest New Drugs. Feb. 2012;30(1):25-36. doi: 10.1007/s10637-010-9510-7. Epub Aug. 3, 2010.
PCT/US2016/023275 International Preliminary Report on Patentability dated Oct. 5, 2017.
Rankin, et al. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. Apr. 2008;15(4):678-85. doi: 10.1038/cdd.2008.21. Epub Feb. 15, 2008.
Rasmussen, et al. Ruthenium-catalyzed cycloaddition of aryl azides and alkynes. Org Lett. Dec. 20, 2007;9(26):5337-9. Epub Dec. 1, 2007.
Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Journal of Clinical Oncology, 22(16), pp. 3432-3433.
Ritter, et al. Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathy. J Clin Invest. Dec. 2006;116(12):3266-76. Epub Nov. 16, 2006.
Rostovtsev, et al. A stepwise huisgen cycloaddition process: copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew Chem Int Ed Engl. Jul. 15, 2002;41(14):2596-9.
Scatena, C.D., et al. Imaging of bioluminescent LNCaP-luc-M6 tumors: a new animal model for the study of metastatic human prostate cancer. Prostate. May 15, 2004:59(3):292-303.
Semenza, GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol. Apr. 2001;13(2):167-71.
Simon, et al. Hypoxia-induced signaling in the cardiovascular system. Annu Rev Physiol. 2008;70:51-71.
Skoulidis, et al., Co-occurring alterations define major subsets of KRAS-mutant lung adenocarcinoma (LUAC) with distinct biology and therapeutic vulnerabilities. Sunday, Apr. 19, 2015. AACR, Presentation Abstract.
Tahir, et al. Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737. Cancer Res. Feb. 1, 2007;67(3):1176-83.
Tazuke, et al. Hypoxia stimulates insulin-like growth factor binding protein 1 (IGFBP-1) gene expression in HepG2 cells: a possible model for IGFBP-1 expression in fetal hypoxia. Proc Natl Acad Sci USA. Aug. 18, 1998;95(17):10188-93.
Thallinger, et al. Mcl-1 is a novel therapeutic target for human sarcoma: synergistic inhibition of human sarcoma xenotransplants by a combination of mcl-1 antisense oligonucleotides with low-dose cyclophosphamide. Clin. Cancer Res. Jun. 15, 2004;10(12 Pt 1):4185-91.
Toffoli, et al. Intermittent hypoxia is a key regulator of cancer cell and endothelial cell interplay in tumours. FEBS J. Jun. 2008;275(12):2991-3002. doi: 10.1111/j.1742-4658.2008.06454.x. Epub Apr. 25, 2008.
Twombly, R. Cancer Surpasses Heart Disease as Leading Cause of Death for All But the Very Elderly. Journal of the National Cancer Institute. Mar. 2, 2005;97(5):330-331.
Uppsala Software Factory—Typical bond lengths. Latest update at Fri Jul. 11, 1997 23:24:54 by TABLE2HTML version 970219/0.5 http://www.greeley.org/-hod/papers/typical_bonds.html [Apr. 8, 2018 11:12:57 AM] (Year: 1997).
U.S. Appl. No. 14/460,848 Office Action dated Jun. 11, 2018.
U.S. Appl. No. 14/864,687 Office Action dated Apr. 18, 2018.
U.S. Appl. No. 14/864,687 Office Action dated Jun. 19, 2018.
U.S. Appl. No. 14/921,573 Office Action dated May 11, 2018.
U.S. Appl. No. 15/074,794 Office Action dated May 11, 2018.
U.S. Appl. No. 15/093,426 Notice of Allowance dated Feb. 27, 2018.
U.S. Appl. No. 15/093,426 Office action dated Jan. 8, 2018.
U.S. Appl. No. 15/093,869 Notice of Allowance dated May 31, 2018.
U.S. Appl. No. 15/093,869 Office action dated Jan. 22, 2018.
U.S. Appl. No. 15/135,098 Notice of Allowance dated Jan. 25, 2018.
U.S. Appl. No. 15/275,118 Office Action dated Jun. 1, 2018.
U.S. Appl. No. 14/864,801 Notice of Allowance dated May 21, 2018.
Ushio-Fukai, et al. Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett. Jul. 18, 2008;266(1):37-52. doi: 10.1016/j.canlet.2008.02.044. Epub Apr. 10, 2008.
Vanarsdale, et al. Molecular Pathways: Targeting the Cyclin D-CDK4/6 Axis for Cancer Treatment. Clin Cancer Res. Jul. 1, 2015;21(13):2905-10. doi: 10.1158/1078-0432.CCR-14-0816. Epub May 4, 2015.
Vinores, et al. Implication of the hypoxia response element of the Vegf promoter in mouse models of retinal and choroidal neovascularization, but not retinal vascular development. J Cell Physiol. Mar. 2006;206(3):749-58.
Walensky, et al. Hydrocarbon-stapled peptides: principles, practice, and progress. J Med Chem. Aug. 14, 2014;57(15):6275-88. doi: 10.1021/jm4011675. Epub Mar. 6, 2014.
Weller, et al. Predicting chemoresistance in human malignant glioma cells: the role of molecular genetic analyses. International journal of cancer 79.6 (1998): 640-644.
Wilkinson-Berka, et al. The role of growth hormone, insulin-like growth factor and somatostatin in diabetic retinopathy. Curr Med Chem. 2006;13(27):3307-17.
Wiseman, et al. Rapid measurement of binding constants and heats of binding using a new titration calorimeter. Anal Biochem. May 15, 1989;179(1):131-7.
Wu, et al. Regiospecific synthesis of 1, 4, 5-trisubstituted-1, 2, 3-triazole via one-pot reaction promoted by copper (I) salt. Synthesis 8 (2005): 1314-1318.
Zhang, et al. Chemopreventive agents induce programmed death-1-ligand 1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated T cell apoptosis. Mol Immunol. Mar. 2008;45(5):1470-6. Epub Oct. 24, 2007.
Zhang, et al. Ruthenium-catalyzed cycloaddition of alkynes and organic azides. J Am Chem Soc. Nov. 23, 2005;127(46):15998-9.
Zhang, et al. Synergistic combination of microtubule targeting anticancer fludelone with cytoprotective panaxytriol derived from panax ginseng against MX-1 cells in vitro: experimental design and data analysis using the combination index method. Am J Cancer Res. Dec. 15, 2015;6(1):97-104. eCollection 2016.
Zhu, et al. Long-term tolerance to retinal ischemia by repetitive hypoxic preconditioning: role of HIF-1alpha and heme oxygenase-1. Invest Ophthalmol Vis Sci. Apr. 2007;48(4):1735-43.
Zhu, et al. Mechanisms of relapse in acute leukaemia: involvement of p53 mutated subclones in disease progression in acute lymphoblastic leukaemia. Br J Cancer. Mar. 1999;79(7-8):1151-7.
Zuluaga, et al. Synergies of VEGF inhibition and photodynamic therapy in the treatment of age-related macular degeneration. Invest Ophthalmol Vis Sci. Apr. 2007;48(4):1767-72.
EP15844140.2 Extended Search Report dated Jun. 6, 2018.
The Rx list webpage for cytarabine, https://web.archive.org/web/20081113060948/https://www.rxlist.com/cytarabine-drug.htm, available Nov. 2008.
U.S. Appl. No. 15/256,130 Office Action dated Jul. 16, 2018.

Related Publications (1)

	Number	Date	Country
	20170281720 A1	Oct 2017	US

Provisional Applications (3)

Number	Date	Country
61723770	Nov 2012	US
61656962	Jun 2012	US
61599328	Feb 2012	US

Continuations (2)

	Number	Date	Country
Parent	14498063	Sep 2014	US
Child	15229517		US
Parent	13767852	Feb 2013	US
Child	14498063		US

Peptidomimetic macrocycles

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

Field of Search

CPC

International Classifications

Disclaimer

Abstract

Description

Claims

CROSS-REFERENCE

US Referenced Citations (596)

Foreign Referenced Citations (256)

Non-Patent Literature Citations (1042)

Related Publications (1)

Provisional Applications (3)

Continuations (2)