SUBSTITUTED 4-(3-AMINOPROP-1-YL)AMINOQUINOLINE ANALOGS AS MODULATORS OF MELANOMA-ASSOCIATED ANTIGEN 11 UBIQUITIN LIGASE

BACKGROUND

Melanoma antigens (MAGEs) are a large (>40 in humans) and highly conserved family of proteins present in all eukaryotes (Ref. 1, 2). MAGEs can be classified into two categories based on their tissue expression pattern (Ref. 2, 3). Two-thirds of MAGEs, including MAGE-A, -B and -C subfamilies are considered type I MAGEs due to their restricted expression in the testis and other reproductive tissues (Refs. 3-6). Conversely, MAGE-D, -E, -F, -G, -H, -L and Necdin subfamilies are type II MAGEs that have broad expression in many tissues (Ref. 1, 2). Both type I and II MAGEs share a conserved domain known as the MAGE homology domain (MHD) involved in protein-protein interactions. MHDs consist of tandem winged-helix motifs (WH-A and WH-B) that feature a helix-turn-helix packed against a three-stranded antiparallel beta-sheet (Refs. 7-9). The overall structures of MHDs are similar between MAGEs, but the relative orientation of WH-A to WH-B can differ (Ref. 8,9).

Although type I MAGEs are typically restricted to expression in the testis, they are often aberrantly expressed in many cancer types and are often referred to as cancer-testis antigens (Ref. 1, 3). The aberrant expression of MAGEs in tumors is not simply an inert consequence of genomic dysregulation, but instead MAGEs play active roles in driving tumorigenesis (Refs. 1, 5, and 10-13). For example, MAGE-A3, -A6 and -A11 are aberrantly expressed in many cancer types, including melanoma, breast, colon and lung cancers, where they are required for cancer cell viability and promote multiple hallmarks of cancer, such as anchorage-independent growth and xenograft tumor growth (Ref. 1, 5, 10, and 14). Recent studies have highlighted an important role of MAGEs in controlling core oncogenic and tumor suppressor pathways in cells, including metabolic rewiring by MAGE-A3/6 through modulation of AMPK and autophagy and promotion of alternative polyadenylation by MAGE-A11 (Ref. 5, 10). In addition, MAGE-F1 is highly amplified in multiple cancer types leading to reduced DNA repair capacity and increased mutational burden in tumors through downregulation of the cytosolic iron-sulfur assembly pathway (Ref. 15). Thus, given the prominent, cancer selective expression of MAGEs and their oncogenic functions, MAGEs have emerged as prime therapeutic targets. However, this effort has been impeded by our limited understanding of how to target these enigmatic proteins.

Growing evidence suggests that MAGEs function as substrate adaptors for E3 ubiquitin ligases (reviewed in Ref. 2). MAGEs bind to specific single-subunit E3 ubiquitin ligases, both RING and HECT type ligases, including MAGE-A1-TRIM31, MAGE-A3-TRIM28, MAGE-A11-HUWE1, MAGE-B18-LNX1, MAGE-D1-PRAJA1, MAGE-F1-NSE1, MAGE-L2-TRIM27 and MAGE-G1-NSE1 (Ref. 8, 10, and 16-18). Importantly, MAGEs alter the function of these ligases by recruiting novel substrates to the ligases for ubiquitination, including MAGE-A3 mediating the ubiquitination of AMPK by TRIM28, MAGE-A11 mediating ubiquitination of PCF11 by HUWE1 and MAGE-F1 mediating ubiquitination of MMS19 by NSE1 (Ref. 5, 10, and 15). In each of these cases, the MAGE functions as ‘protein glue’ that mediates recruitment of the substrate to the ligase complex for ubiquitination. Thus, MAGEs reprogram single-subunit ubiquitin ligases. Notably, the specific MAGE bound to a ligase can dictate distinct substrates and functions. For example, both MAGE-F1 and MAGE-G1 bind the NSE1 ligase. However, these MAGEs have distinct substrates with opposing cellular functions in modulating DNA repair pathways (Ref. 8, 15, and 19). In many ways MAGEs have similar properties to Cullin-RING Ligase (CRL) adaptor protein families, such as F-box, BTB, DCAF and SOCS box proteins, which allow modularity, functional diversification and adaptability of CRLs20. However, unlike CRL adaptors, the molecular and structural basis of how MAGEs recognize substrates has been unknown.

Thus, although testis-restricted melanoma antigen (MAGE) proteins are frequently hijacked in cancer and play a critical role in tumorigenesis, the mechanism by which MAGEs recognize their targets is not previously known in the prior art and has impeded the development of MAGE-directed therapeutics.

Despite advances in cancer research and research directed to a better understanding of MAGE proteins, there is still a scarcity of compounds that are both potent, efficacious, and selective inhibitors of MAGE proteins, in particular, MAGE-A11:substrate interactions, and also effective in the treatment of disorders associated with MAGE proteins, e.g., a cancer. These needs and other needs are satisfied by the present disclosure.

SUMMARY

In accordance with the purpose(s), as embodied and broadly described herein, the present disclosure provides compounds that are useful as inhibitors of MAGE-A11:substrate interaction, methods of making same, pharmaceutical compositions including the same, and methods of treating a disorder associated with a MAGE-A11 dysfunction, e.g., a cancer, using same. The present disclosure further relates to peptides useful as inhibitors of MAGE-A11:substrate interaction, methods of making same, pharmaceutical compositions including same, and methods of treating a disorder associated with a MAGE-A11 dysfunction, e.g., a cancer, using same.

Disclosed are compounds having a structure represented by a formula:

embedded image

wherein m is selected from 2, 3, and 4; wherein R¹is selected from hydrogen, halogen, C1-C10 haloalkyl, C1-C10 alkoxy, C1-C10 aminoalkyl, C1-C10 alkylamino, C1-C10 hydoxyalkyl, C1-C10 alkyl, -Q-Ar², -Q-Cy¹, —Ar², and —Cy¹; wherein Q is selected from —(CH₂)_n— and —O—; wherein n is selected from 1 and 2; wherein the Ar¹is selected from phenyl, benzyl, indolyl, benzo[d][1,3]dioxolyl naphthyl, and anthracenyl; wherein the Ar¹is substituted with 0, 1, or 2 groups independently selected from halogen, —SF₅, —CN, —N₃, —NH₂, —OH, —CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydoxyalkyl, and C1-C3 alkyl; wherein the Cy¹is C3-C8 cycloalkyl; and wherein the Cy¹is substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF₅, —CN, —N₃, —NH₂, —OH, —CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydoxyalkyl, and C1-C3 alkyl; wherein R²is selected from H and C1-C3 alkyl; wherein R³is selected from H, C1-C3 alkyl, and —(CH₂)_p—Ar²; wherein p is selected from 1 and 2; wherein Ar²is selected from a phenyl, indolyl, benzo[d][1,3]dioxolyl, naphthyl, and anthracenyl; wherein the Ar²is substituted with 0, 1, or 2 groups independently selected from halogen, —SF₅, —CN, —N₃, —NO₂, —OH, —CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydoxyalkyl, and C1-C3 alkyl; or a pharmaceutically acceptable salt thereof.

Also disclosed are peptides having a structure given by the sequence:

FLVVVHQIRQLXQ,

wherein X is a substituted phenylalanine analog having the structure given by the formula:

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wherein q is selected from 0, 1, and 2; wherein each of R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³, and R¹⁰⁴is independently selected from hydrogen, halogen, —SF₅, —CN, —N₃, —NH₂, —OH, —CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydoxyalkyl, and C1-C3 alkyl.

Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of one or more disclosed compounds, or pharmaceutically acceptable salt thereof; a therapeutically effective amount of one or more disclosed peptides, or pharmaceutically acceptable salt thereof; or combinations thereof; and a pharmaceutically acceptable carrier.

Also disclosed are methods for the treatment of a disorder associated with MAGE-A11 dysfunction in a mammal comprising the step of administering to the mammal a therapeutically effective amount of one or more disclosed compounds, or pharmaceutically acceptable salt thereof; a therapeutically effective amount of one or more disclosed peptides, or pharmaceutically acceptable salt thereof; or combinations thereof.

Also disclosed are methods for inhibiting a MAGE-A11:substrate interaction in a mammal comprising the step of administering to the mammal a therapeutically effective amount of one or more disclosed compounds, or pharmaceutically acceptable salt thereof; a therapeutically effective amount of one or more disclosed peptides, or pharmaceutically acceptable salt thereof; or combinations thereof.

Also disclosed are methods for inhibiting MAGE-A11 activity in at least one cell, comprising the step of contacting the cell with an effective amount of one or more disclosed compounds, or pharmaceutically acceptable salt thereof; an effective amount of one or more disclosed peptides, or pharmaceutically acceptable salt thereof; or combinations thereof.

Also disclosed are uses of a disclosed compound, or a pharmaceutically acceptable salt thereof; a disclosed peptide, or a pharmaceutically acceptable salt thereofl; a disclosed product of making a disclosed compound and/or a product of making a disclosed peptide, or a pharmaceutically acceptable salt thereof; or a disclosed pharmaceutical composition including a therapeutically effective amount of one or more disclosed compounds, or pharmaceutically acceptable salt thereof; a therapeutically effective amount of one or more disclosed peptides, or pharmaceutically acceptable salt thereof; or combinations thereof.

Also disclosed are uses of a one or more disclosed compounds, or pharmaceutically acceptable salt thereof; one or more disclosed peptides, or pharmaceutically acceptable salt thereof; or combinations thereof; in the manufacture of a medicament for the treatment of a disorder associated with a MAGE-A11 dysfunction in a mammal.

Also disclosed are methods for the manufacture of a medicament to inhibit a MAGE-A11:substrate interaction in a mammal including combining a pharmaceutically acceptable carrier or diluent and one or more disclosed compounds, or pharmaceutically acceptable salt thereof; one or more disclosed peptides, or pharmaceutically acceptable salt thereof; or combinations thereof.

Also disclosed are kits including at least one disclosed compound, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, and one or more of: (a) at least one agent known to increase MAGE-A11 activity; (b) at least one agent known to decrease MAGE-A11 activity; (c) at least one agent known to treat a disorder of uncontrolled cellular proliferation; (d) instructions for treating a disorder of uncontrolled cellular proliferation; or (e) instructions for treating a disorder associated with MAGE-11A dysfunction.

While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE FIGURES

Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. Moreover, in the drawings, like reference numerals designate corresponding parts throughout the several views.

FIGS. 1A-1H show representative data pertaining to characterization of MAGE-A11 interaction with substrates. FIG. 1A shows the MAGE-A11 recognition sequence in PCF11 is within amino acids 653-702. HEK293FT cells stably expressing FLAG-vector or FLAG-MAGE-A11 were transfected with PCF11 wild-type or PCF11 653-702 deletion construct for 48 hr followed by IP with anti-FLAG, SDS-PAGE and immunoblotting for anti-Myc. FIGS. 1B and 1C show data pertaining to mapping of MAGE-A11-interacting motif in PCF11 by TR-FRET. Sequences of PCF11 degron motif and tested eight PCF11 peptides are shown FIG. 1B. The binding activity of each peptide to GST-MAGE-A11 by TR-FRET is shown FIG. 1C. FIG. 1D shows data pertaining to validation of PCF11 peptide binding to MAGE-A11 using a thermal stability assay. Thermal unfolding of MAGE-A11 was monitored with increasing concentrations of PCF11_6 peptide. FIG. 1E shows data pertaining to alanine scanning mutagenesis of PCF11_6 peptide binding to GST-MAGE-A11 as determined using a TR-FRET assay as described herein.

FIG. 1F show data pertaining to relative TR-FRET affinity measurements of PCF11 degron peptide variants library (248 peptides). Shading indicates relative binding affinity normalized at each position. The circles indicate the sequence of the natural PCF11 degron peptide. FIG. 1G show a comparison of 16 predicted MAGE-A11-binding motifs. FIG. 1H show data pertaining to binding of recombinant GST-MAGE-A11 to in vitro translated Myc-RACGAP1, ANKRD65 and ZBTB7C.

FIGS. 2A-2G show data pertaining to the crystal structure of MAGE-A11:PCF11 and identification of the MAGE substrate binding cleft. FIG. 2A show representative data pertaining to MAGE-A11 directly interacting with PCF11 through its MHD. In vitro translated Myc-MAGE-A11 MHD, but not N-terminal fragment, binds to recombinant GST-PCF11. FIG. 2B show a representation of a model of the overall structure of MAGE-A11 MHD with PCF11 degron peptide. The alpha-helical PCF11 degron peptide binds into SBC at interface of WH-A and WH-B motifs of MAGE-A11 MHD. PCF11 peptide is shown in darker grey and MAGE-A11 in lighter grey. FIG. 2C show a representative space filling model of MAGE-A11 atoms within 5 Å of PCF11 are shown in darker grey to indicate the SBC region. Residues in the SBC that are mutated in this study are labeled and shown in a lighter grey. FIG. 2D shows a structural model of substrate interaction in which interaction is achieved by hydrophobic interactions along the alpha-helical interface of PCF11 with MAGE-A11 SBC. FIG. 2E shows representative data obtained using myc-tagged MAGE-A11 wild-type or mutants that were in vitro translated and followed by an in vitro binding assay with recombinant GST-PCF11 637-702 amino acids, SDS-PAGE and immunoblotting for anti-Myc. FIG. 2F shows representative data suggesting that MAGE-A11 SBC is crucial for PCF11 substrate binding, but not HUWE1 E3 ligase binding, in cells. HEK293FT cells stably expressing FLAG-vector, FLAG-MAGE-A11 wild-type or mutants were subjected to pull-down with anti-FLAG followed by SDS-PAGE and immunoblotting for anti-HUWE1 and anti-PCF11. FIG. 2G show representative data obtained using TR-FRET binding assays of GST-MAGE-A11 with PCF11 peptide (FLVVVHQIRQLF*Q) containing phenylalanine, 3-methyl-phenylalanine or 4-cyano-phenylalanine at the indicated position.

FIGS. 3A-3G show representative data indicating that mutation of MAGE-A11 SBC disrupts its oncogenic activity. FIG. 3A shows representative data suggesting that MAGE-A11-induced ubiquitination of PCF11 depends on its substrate recognition by MAGE-A11 SBC. Ubiquitinated proteins from FLAG-vector, FLAG-MAGE-A11 wild-type or SBC mutants stably expressing HEK293FT cells were treated with 10 μM MG132 for 4 hr and isolated with tandem ubiquitin binding entity-agarose followed by SDS-PAGE and immunoblotting for endogenous PCF11. FIG. 3B shows representative data suggesting that MAGE-A11 SBC mutants fail to promote proliferation of MAGE-A11 knockout DAOY cells. Wild-type, MAGE-A11-knockout DAOY cells or those reconstituted with MAGE-A11 were counted for cell proliferation at the indicated time points. FIGS. 3C, 3D, and 3E show representative data suggesting that MAGE-A11 knockout DAOY cells reconstituted with MAGE-A11 SBC mutants reduced clonogenic growth and xenograft tumor growth of MAGE-A11 knockout DAOY cells. Stable expression of wild-type MAGE-A11 or SBC mutants in MAGE-A11-knockout DAOY cells were assayed for clonogenic growth (FIG. 3C) and xenograft tumor growth in mice (n=6 per group). Tumor burden (FIG. 3D) and tumor weight (FIG. 3E) are shown. Data are mean±SD. Asterisks indicate p<0.05. FIG. 3F show representative data suggesting that MAGE-A11 M341R mutant fails to promote mRNA 3′UTR shortening. Transcriptome analysis of tumors (n=3 per group) from MAGE-A11 knockout DAOY cells stably expressing FLAG-MAGE-A11 wild-type or M341R mutant was determined and scatterplot of Percentage of Distal polyA site Usage Index (PDUI) is shown. False discovery rate ≤0.05 and ΔPDUIs≥0.2 are colored. The shift towards distal polyadenylation site is significant (p=5.9×10⁻¹⁶, binomial test). FIG. 3G show representative RNA-seq density plots.

FIGS. 4A-4G show representative data indicating that the SBC region mediates substrate recognition and specificity across the MAGE family. FIG. 4A shows a representative space filling structural model indicating sequence conservation of MAGE-A genes mapped onto MAGE-A11:PCF11 structure. FIG. 4B show a representative structural model showing comparison of MAGE-A3 and -A11 SBC that reveals key sequence differences in critical substrate binding residues. FIG. 4C shows representative obtained using in vitro GST-pulldown assays. The data reveal that GST-PCF11 binds in vitro translated Myc-MAGE-A11, but no other Myc-MAGE-A protein. FIGS. 4D, 4E, 4F, and 4G show data indicating that mutation of MAGE-A3 or -F1 SBC disrupts binding to their respective substrates AMPK and MMS19, not the E3 ligases TRIM28 and NSE1. Surface representations of MAGE-A3 (protomer model formed by PDB ID 4V0P for residues 1-296 and MAGE-A11 based homology model for C-terminal residues 297-311) (FIG. 4D) and MAGE-F1 (SWISS-MODEL based on PDB:4V0P) (FIG. 4F) show positioning of SBC residues mutated. Consistent with FIG. 2c, MAGE atoms within 5 Å of modeled PCF11 (based on superimposition of MAGE-A11:PCF11) are colored cyan. Residues in the SBC that are mutated are labeled and colored yellow. Co-IP of MAGEs with substrates and ligases were determined in Hela cells (FIG. 4F) or HEK293FT cells (FIG. 4G) upon transfection of the indicated constructs for 48 hr, IP with anti-Myc, SDS-PAGE and immunoblotting for indicated proteins.

FIGS. 5A-5G show representative data pertaining to disclosed small molecule inhibitors targeting MAGE-A11. FIG. 5A show representative obtained from 500 analogs from 9 scaffolds that were tested in dose response TR-FRET assays for disruption of MAGE-A11 binding to PCF11 identified the quinoline scaffold. FIG. 5B show a chemical structure of a representative disclosed compound, SJ521054. FIG. 5C show representative data obtained using a TR-FRET competition assay using indicated concentrations of quinoline series compounds for disruption of MAGE-A11:PCF11 binding. FIG. 5D show representative data indicating that SJ521054 inhibits MAGE-A11 binding to PCF11 in cell lysate. FLAG-MAGE-A11 stably expressing HEK293FT cell lysates were incubated with 100 μM SJ521054 for 24 hours and then subjected to pull-down with anti-FLAG followed by SDS-PAGE and immunoblotting for endogenous PCF11, and quantitated (n=4). *=p<0.05 (student's t-test). FIG. 5E show representative data indicating that SJ521054 blocks PCF11 degradation by MAGE-A11. HEK293FT cells stably expressing FLAG-vector or FLAG-MAGE-A11 were treated with indicated concentrations of SJ521054 for 24 hours before immunoblotting. FIG. 5F show representative data indicating that SJ521054 reduces viability of MAGE-A11 expressing DAOY cancer cells. MAGE-A11-knockout DAOY cells or those reconstituted with MAGE-A11 were treated with indicated concentrations of SJ521054 and cell viability was measured by alamarBlue assay 24 hours later. FIG. 5G show representative data indicating derivatives of SJ521054 that were synthesized and tested by TR-FRET competition assays with SJ1008066 had improved activity.

FIGS. 6A-6E show representative data pertaining to identification of the degron motif in PCF11 required for MAGE-A11 binding. FIG. 6A shows a representative schematic illustration of a disclosed TR-FRET MAGE-A11:PCF11 peptide binding assay. To monitor the MAGE-A11 and PCF11 interaction, recombinant GST-tagged MAGE-A11 MHD was incubated with FAM-labeled and unlabeled series of PCF11 peptides and TR-FRET signal was quantified. FIG. 6B show representative analysis of the Tm-shift in shown in FIG. 1D obtained by plotting the temperature at 50% relative fluorescence. FIGS. 6C and 6D show a schematic representation of alanine scanning mutations in PCF11 degron peptide. The amino acid sequences of PCF11 degron are listed with alanine substitutions for each residue. IC₅₀values for each mutant by TR-FRET (FIG. 6C) and relative binding (FIG. 6D) are shown. FIG. 6E shows a representation of the MAGE-A11 binding motif sequence and weighted position matrix.

FIGS. 7A-7D show pertaining to the characterization of the MAGE-A11 SBC in recognition of PCF11. FIGS. 7A-7B show representative electron-density maps of PCF11 peptide bound to MAGE-A11. Shown are simulated annealing 2F_o-F_ccomposite omit maps contoured at 1σ. FIG. 7C shows a 2D representation of MAGE-A11-PCF11 interactions by Ligplot⁺(Ref. 44). FIG. 7D shows representative IC₅₀results obtained using TR-FRET binding assay of GST-MAGE-A11 with PCF11 peptide (FLVVVHQIRQLF*Q) containing the indicated phenylalanine substitutions at the indicated position.

FIG. 8 shows a representative sequence alignment of MAGE-A3, -A11 and -F1 MHDs. Sequence alignment and secondary structure of MHDs from MAGE-A11, -A3 and -F1. Key conserved interaction residues within the SBC chosen for mutagenesis are shown. Residues in blue highlight substitutions within the SBC that likely contribute to substrate binding selectivity.

FIGS. 9A-9G show representative data obtained from a chemical screen of disclosed small molecular inhibitors of MAGE-A11:PCF11 interaction. FIG. 9A shows a summary of high-throughput screening approach disclosed herein. FIG. 9B representative results obtained from a primary screen for all 31,407 compounds screened at a single concentration (15 μM) using a TR-FRET assay. Positive controls (data shown having about 100% activity); negative control (DMSO, lighter grey centered on about 0% activity), and screening compounds (black). FIG. 9C shows the Z′-factor in the order of plates screened in the primary screen. FIG. 9D shows a representative percentage activity scatterplot for 797 analogs from five quinoline series screened at single concentration (15 μM) as determined using a TR-FRET assay. FIG. 9E shows representative data obtained using FLAG-MAGE-A11 stably expressing HEK293FT cell lysates that were incubated with 100 μM of the indicated quinoline compounds for 24 hours and then subjected to pull-down with anti-FLAG followed by SDS-PAGE and immunoblotting for endogenous PCF11. Note: SJ521054 (0.40 μM), SJ311286 (1.16 μM) and SJ311270 (0.58 μM) are active inhibitors by TR-FRET and SJ311280 (4.07 μM), SJ311281 (5.58 μM) and SJ311284 (20.60 μM) show low activity by TR-FRET. FIG. 9F shows representative data indicating that treatment of SJ521054 reduces viability of MAGE-A11 expressing HEK293FT cells. HEK293FT cells stably expressing FLAG-vector or FLAG-MAGE-A11 were treated with the indicated concentrations of SJ521054 and cell viability was measured by alamarBlue assay 24 hours later. FIG. 9G shows representative chemical structures of disclosed SJ521054 derivative compounds. IC₅₀, solubility, Caco-2 permeability and c Log P values of each compound are shown.

Additional advantages of the disclosure will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the disclosure. The advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure, as claimed.

DETAILED DESCRIPTION

Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

All publications and patents cited in this specification are cited to disclose and describe the methods and/or materials in connection with which the publications are cited. All such publications and patents are herein incorporated by references as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. Such incorporation by reference is expressly limited to the methods and/or materials described in the cited publications and patents and does not extend to any lexicographical definitions from the cited publications and patents. Any lexicographical definition in the publications and patents cited that is not also expressly repeated in the instant application should not be treated as such and should not be read as defining any terms appearing in the accompanying claims. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided could be different from the actual publication dates that may need to be independently confirmed.

It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

Aspects of the present disclosure will employ, unless otherwise indicated, techniques of molecular biology, microbiology, organic chemistry, biochemistry, physiology, cell biology, blood vessel biology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.

Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.

Definitions

As used herein, terms such as “by”, “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” should be interpreted to included examples and aspects encompassed by the terms “consisting essentially of” and “consisting of” as well as examples and aspects that include the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof as would commonly be encompassed by terms such as “comprising,” “comprises”, and “comprised of.”

As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items. Expressions such as “at least one of,” when preceding a list of elements, modify the entire list of elements and do not modify the individual elements of the list.

As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound,” “a peptide,” or “a cell,” including, but not limited to, two or more such compounds, peptides, or cells

Reference to “a/an” chemical compound, peptide, and cell each refers to one or more molecules of the chemical compound, peptide, and cell rather than being limited to a single molecule of the chemical compound, peptide, and cell. Furthermore, the one or more molecules may or may not be identical, so long as they fall under the category of the chemical compound, peptide, and cell. Thus, for example, “a” peptide is interpreted to include one or more peptide molecules of the peptide, where the peptide molecules may or may not be identical.

It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

Where a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y′”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of’ the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

As used herein, “about,” “approximately,” “substantially,” and the like, when used in connection with a numerical variable, can generally refer to the value of the variable and to all values of the variable that are within the experimental error (e.g., within the 95% confidence interval for the mean) or within +/−10% of the indicated value, whichever is greater. As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” can mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

As used herein, “melanoma antigen, family A, 11,” “MAGEA11,” and “MAGE-A11” can be used interchangeably and refer to an enzyme encoded by a gene in humans with a cytogenetic location of Xq28 and a genomic coordinate of X:149,688, 192-149,717,267 (Homo sapiens Annotation Release 109, GRCh38). It has an intracellular location within the nucleus and cytoplasm. MAGE-A11 has also been referred to as Cancer/testis antigen 1.11 and MAGE-11 antigen. It is believed to be expressed in tumors such as melanoma, head and neck squamous cell carcinoma, lung carcinoma and breast carcinoma. Moreover, it is believed to be expressed in testis, ovary, prostate, cancerous prostate, breast and adrenal tissue.

As used herein, “administering” can refer to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, intracavernous, intrathecal, intravireal, intracerebral, and intracerebroventricular, intratympanic, intracochlear, rectal, vaginal, by inhalation, by catheters, stents or via an implanted reservoir or other device that administers, either actively or passively (e.g. by diffusion) a composition the perivascular space and adventitia. For example a medical device such as a stent can contain a composition or formulation disposed on its surface, which can then dissolve or be otherwise distributed to the surrounding tissue and cells. The term “parenteral” can include subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

As used herein, “therapeutic agent” can refer to any substance, compound, molecule, and the like, which can be biologically active or otherwise can induce a pharmacologic, immunogenic, biologic and/or physiologic effect on a subject to which it is administered to by local and/or systemic action. A therapeutic agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed. A therapeutic agent can be a secondary therapeutic agent, or in other words, the component(s) of a composition to which an additional part and/or other effect of the composition is attributed. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit including an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can include one or multiple documents, and are meant to include future updates.

As used herein, “attached” can refer to covalent or non-covalent interaction between two or more molecules. Non-covalent interactions can include ionic bonds, electrostatic interactions, van der Walls forces, dipole-dipole interactions, dipole-induced-dipole interactions, London dispersion forces, hydrogen bonding, halogen bonding, electromagnetic interactions, TT-TT interactions, cation-IT interactions, anion-IT interactions, polar IT-interactions, and hydrophobic effects.

As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and juvenile subjects, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

As used herein, the terms “treating” and “treatment” can refer generally to obtaining a desired pharmacological and/or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as a cancer. The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder, or condition. The term “treatment” as used herein can include any treatment of a cancer in a subject, particularly a human and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and/or its symptoms or conditions. The term “treatment” as used herein can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and/or those in which the disorder is to be prevented. As used herein, the term “treating”, can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

As used herein, “dose,” “unit dose,” or “dosage” can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and/or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.

As used herein, “therapeutic” can refer to treating, healing, and/or ameliorating a disease, disorder, condition, or side effect, or to decreasing in the rate of advancement of a disease, disorder, condition, or side effect.

As used herein, “effective amount” can refer to the amount of a disclosed compound or pharmaceutical composition provided herein that is sufficient to effect beneficial or desired biological, emotional, medical, or clinical response of a cell, tissue, system, animal, or human. An effective amount can be administered in one or more administrations, applications, or dosages. The term can also include within its scope amounts effective to enhance or restore to substantially normal physiological function.

As used herein, the term “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts. In the case of treating a particular disease or condition, in some instances, the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to halt the progression of the disease permanently. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease. The desired response to treatment of the disease or condition also can be delaying the onset or even preventing the onset of the disease or condition.

For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the invention (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.

A response to a therapeutically effective dose of a disclosed compound and/or pharmaceutical composition, for example, can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied for example by increasing or decreasing the amount of a disclosed compound and/or pharmaceutical composition, by changing the disclosed compound and/or pharmaceutical composition administered, by changing the route of administration, by changing the dosage timing and so on. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

As used herein, the term “prophylactically effective amount” refers to an amount effective for preventing onset or initiation of a disease or condition.

As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

The term “pharmaceutically acceptable salts”, as used herein, means salts of the active principal agents which are prepared with acids or bases that are tolerated by a biological system or tolerated by a subject or tolerated by a biological system and tolerated by a subject when administered in a therapeutically effective amount. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to; sodium, potassium, calcium, ammonium, organic amino, magnesium salt, lithium salt, strontium salt or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to; those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.

The term “pharmaceutically acceptable ester” refers to esters of compounds of the present disclosure which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Examples of pharmaceutically acceptable, non-toxic esters of the present disclosure include C 1 -to-C 6 alkyl esters and C 5 -to-C 7 cycloalkyl esters, although C 1 -to-C 4 alkyl esters are preferred. Esters of disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable esters can be appended onto hydroxy groups by reaction of the compound that contains the hydroxy group with acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable esters are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine and an alkyl halide, for example with methyl iodide, benzyl iodide, cyclopentyl iodide or alkyl triflate. They also can be prepared by reaction of the compound with an acid such as hydrochloric acid and an alcohol such as ethanol or methanol.

The term “pharmaceutically acceptable amide” refers to non-toxic amides of the present disclosure derived from ammonia, primary C 1 -to-C 6 alkyl amines and secondary C 1 -to-C 6 dialkyl amines. In the case of secondary amines, the amine can also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C 1 -to-C 3 alkyl primary amides and C 1 -to-C 2 dialkyl secondary amides are preferred. Amides of disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable amides can be prepared from compounds containing primary or secondary amine groups by reaction of the compound that contains the amino group with an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable amides are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine, a dehydrating agent such as dicyclohexyl carbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine, for example with methylamine, diethylamine, and piperidine. They also can be prepared by reaction of the compound with an acid such as sulfuric acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid under dehydrating conditions such as with molecular sieves added. The composition can contain a compound of the present disclosure in the form of a pharmaceutically acceptable prodrug.

The term “pharmaceutically acceptable prodrug” or “prodrug” represents those prodrugs of the compounds of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. Prodrugs of the present disclosure can be rapidly transformed in vivo to a parent compound having a structure of a disclosed compound, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).

As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

The term “contacting” as used herein refers to bringing a disclosed compound or pharmaceutical composition in proximity to a cell, a target protein, or other biological entity together in such a manner that the disclosed compound or pharmaceutical composition can affect the activity of the a cell, target protein, or other biological entity, either directly; i.e., by interacting with the cell, target protein, or other biological entity itself, or indirectly; i.e., by interacting with another molecule, co-factor, factor, or protein on which the activity of the cell, target protein, or other biological entity itself is dependent.

As used herein, nomenclature for compounds, including organic compounds, can be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature. When one or more stereochemical features are present, Cahn-Ingold-Prelog rules for stereochemistry can be employed to designate stereochemical priority, E/Z specification, and the like. One of skill in the art can readily ascertain the structure of a compound if given a name, either by systemic reduction of the compound structure using naming conventions, or by commercially available software, such as CHEMDRAW™ (Cambridgesoft Corporation, U.S.A.).

It is understood, that unless otherwise specified, temperatures referred to herein are based on atmospheric pressure (i.e. one atmosphere).

Described herein are compounds and peptides that have therapeutic or clinical utility. Also described herein are methods of synthesizing the disclosed compounds and peptides. Also described herein are methods of administering the disclosed compounds and peptides to a subject in need thereof. In some aspects, the subject can have a cancer. Other compositions, compounds, methods, features, and advantages of the present disclosure will be or become apparent to one having ordinary skill in the art upon examination of the following drawings, detailed description, and examples. It is intended that all such additional compositions, compounds, methods, features, and advantages be included within this description, and be within the scope of the present disclosure.

Compounds.

In various aspects, the present disclosure relates to compounds useful as inhibitors of MAGE-A11:substrate interaction. Disclosed are compounds having a structure represented by a formula:

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In a further aspect, m is selected from 2 and 3. In a still further aspect, m is 1. In a yet further aspect, m is 2. In an even further aspect, m is 3. In yet further aspect, m is selected from 1 and 3.

In a further aspect, n is 1. In a still further aspect, n is 2.

In a further aspect, p is 1. In a still further aspect, p is 2.