Patent Application
20140256776
Hematological cancer includes leukemia, lymphoma, and myeloma. Leukemia is a type of cancer of blood or bone marrow characterized by an abnormal increase of immature leukocytes. The exact cause of leukemia is unknown; however, it generally results from DNA mutations in stem cells.
Leukemia is the most common malignant tumor in children (Leukemia in Children). Among all cancers, leukemia is most common and the leading cause of death for children and teens under 20 years old (Blood Cancers: Leukemia, Lymphoma, and Myeloma). Although leukemia can be classified into a large variety of groups, one of the most commonly used methods is to classify leukemia into four major subtypes: acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) (Types of Leukemia, National Cancer Institute).
Since it is not possible to remove leukemia via surgery, standard treatment options for leukemia are chemotherapy and radiotherapy. Among the four major subtypes, CML may be treated with the introduction of imatinib (Gleevec) into chemotherapy with some success. Unfortunately, CML only accounts for about 15% of adult leukemia (Faderl et al, 1999). Other leukemia patients still rely on traditional chemotherapeutic drugs (e.g., cisplatin), most of which are cytotoxic in nature.
Cytotoxic drugs act to disrupt cell proliferation by directly destroying cellular DNA, incorporating into the DNA template and interfering with DNA synthesis, inhibiting microtubule assembly/disassembly, impairing nucleic acid synthesis, or disrupting protein synthesis. Unfortunately, cytotoxic drugs function in a non-specific manner and kill both cancer cells and normal cells, resulting in severe adverse side effects for patients. Further, by interfering with DNA synthesis, cytotoxic drugs may also induce new DNA mutations that could result in the occurrence of new cancers (Carew et al., 2003; Sturm et al., 2003).
Given the lack of an effective treatment option and the negative side effects associated with current treatment options there is a need to develop a new generation of target-specific drugs for the treatment of leukemia and other cancers with improved therapeutic benefits and reduced side effects.
One aspect of the present disclosure relates to methods of treating cancer by administering one or more compounds disclosed herein or a composition or pharmaceutical formulation thereof.
Another aspect relates to the use of one or more compounds disclosed herein, or a composition or pharmaceutical formulation thereof, in the manufacture of a medicament for the treatment of a cancer. In certain embodiments, the cancer is breast cancer, central nervous system cancer, colon cancer, prostate cancer, lung cancer, leukemia, renal cancer, ovarian cancer, melanoma, liver cancer, and/or cervical cancer. In certain embodiments, when the cancer is leukemia, the type of leukemia may include, but is not limited to, acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), CML (imitinib resistant), multiple myeloma, B-cell myelomonocytic leukemia, T-cell myelomonocytic leukemia, biphenotypic B-cell leukemia, and/or lymphoma.
Another aspect described herein relates to a method of treating a condition regulatable by a transcription factor and/or cofactor comprising administering to the subject a therapeutically effective amount of one or more compounds disclosed herein or a composition or pharmaceutical formulation thereof.
Another aspect relates to the use of one or more compounds disclosed herein or a composition or pharmaceutical formulation thereof in the manufacture of a medicament for the treatment of a condition regulatable by a transcription factor and/or cofactor.
FIG. 1—Growth inhibition of REH, HL60, and Nalm-6 leukemia cell lines in the presence of different concentrations of YT30 and inactive YT19.
FIG. 2—Cumulative survival of BALB/c nude mice bearing acute lymphoblastic leukemia injected with YT30 or solvent control.
I. Compounds
In certain embodiments, the compounds disclosed herein comprise a structure of Formula I:
including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, wherein:
R11-R19 and R110 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, amino, alkylamino, dialkylamino, arylamino, heteroarylamino, hydroxy, haloalkyl, and halogen, and optionally, two or more substituents of R11-R19 and R110 combine together to form a ring of up to 12 atoms;
L11 and L13 are linking groups each independently selected from the group consisting of amino, alkylamino, arylamino, oxa, keto, NHC(═O), NR(C═O), S(═O) and —S(═O)2; and
L12 is a linking group selected from the group consisting of a chain of up to 10 carbon atoms, wherein up to three atoms are replaced with one or more hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur atom, and said one or more hetero atoms are optionally further substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzo, hydroxy, alkoxy, aryloxy, oxa, keto, amido, sulfonamido, and fluoro. In certain of these embodiments, the compounds are transcription factor modulators.
In certain embodiments:
R11, R15, R16, and R110 are each independently selected from the group consisting of NH2 and H, at least one of R11 and R15 is H, and at least one of R16 and R110 is H;
R12 and R14 are each independently selected from the group consisting of H, aryl (e.g. phenyl), alkyl (e.g. methyl, ethyl, isopropyl), hydroxyl, and arylcarbonyl (e.g. phenyl carbonyl);
R13 is selected from the group consisting of H, alkylamino (e.g. dimethyl amino), arylcarbonyl (e.g. phenyl carbonyl) and aryl (e.g. phenyl);
R17 and R19 are each independently selected from the group consisting of H, halogen (e.g. Br, F), heteroaryl (e.g. pyridinyl), alkoxy (e.g. —OCH3), and haloalkyl (e.g. CF3);
R18 is selected from the group consisting of H and halogen (e.g. Br);
-L11- and -L13- are independently —NH—C(═O)— or —C(═O)—NH—; and
-L11-L12-L13- is a symmetric structure of —NH—C(═O)-L12-C(═O)—NH—, or an asymmetric structure of —NHC(═O)-L12-NH—C(═O)—, or —C(═O)—NH-L12-C(═O)—NH—.
Embodiments of compounds of Formula I include, without limitation, the compounds listed in Table 1.
In certain embodiments, the compounds disclosed herein comprise a structure of Formula II:
including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, wherein:
R21 and R22 are each independently selected from the group consisting of aryl and heteroaryl.
In certain embodiments:
R21 is selected from the group consisting of heteroarylalkoxy (e.g. wherein alkoxy is C1-C2 alkoxy, and heteroaryl is pyridinyl or benzopyrrolyl), heteroarylalkyl (e.g. wherein alkyl is C1-C2 alkyl, and heteroaryl is pyridinyl or benzopyrrolyl), and heteroaryl (e.g. pyridinyl); and
R22 is aryl (e.g. aminophenyl). In certain of these embodiments, the compounds are transcription factor modulators.
Embodiments of compounds of Formula II include, without limitation, the compounds listed in Table 2.
In certain embodiments, the compounds disclosed herein comprise a structure of Formula V:
including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, wherein:
R51 and R52 are each independently selected from the group consisting of alkyl, aryl, and heteroaryl. In certain of these embodiments, the compounds are transcription factor modulators.
In certain embodiments:
Embodiments of compounds of Formula V include, without limitation, the compound listed in Table 3.
In certain embodiments, the compounds disclosed herein comprise a structure of Formula VI:
including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, wherein:
R61 and R62 are independently selected from the group consisting of aryl, and heteroaryl. In certain of these embodiments, the compounds are transcription factor modulators.
In certain embodiments:
R61 is selected from the group consisting of heteroaryl (e.g. benzopyrrolyl, benzopyrrolyl substituted with halogen (e.g. Br), haloalkyl (e.g. CF3), or aryl (e.g. phenyl); and furanyl substituted with aryl (e.g. phenyl)), heteroarylalkyl (e.g. wherein alkyl is C2-alkyl, and heteroaryl is benzopyrrolyl), and heteroarylalkoxy (e.g. wherein alkoxy is C1-alkoxy, and heteroaryl is pyridinyl); and
R62 is aryl (e.g. aminophenyl).
Embodiments of compounds of Formula VI include, without limitation, the compounds listed in Table 4.
In certain embodiments, the compounds disclosed herein comprise a structure of Formula VII:
including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, wherein:
R71 and R72 are each independently selected from the group consisting of aryl, and heteroaryl; and
L71 has a structure of -L72-L73-L74- , wherein:
In certain of these embodiments, the compounds are transcription factor modulators.
In certain embodiments:
R71 is heteroaryl (e.g. benzopyrrolyl);
R72 is aryl (e.g. aminophenyl); and
L71 is:
Embodiments of compounds of Formula VII include, without limitation, the compounds listed in Table 5.
In another embodiment, the compounds disclosed herein comprise a structure of Structure I:
including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, wherein:
A and B rings are each independently selected from the group consisting of phenyl, pyridyl and N-alkylated pyridyl rings;
R1-R5 are each independently selected from the group consisting of hydrogen, halogen, and haloalkyl, wherein at least one or two of R1-R5 are halogen and/or haloalkyl;
X1 and X2 are independently selected from —NHC(═O)— or —C(═O)—NH—; and
L1 is —(CH2)n—, where n is 4, 5, 6, 7, or 8, where one or more —CH2— moieties are optionally replaced with one or more substituents selected from the group consisting of —O—, —S—, —C(═O)—, —S(═O)—, —S(═O)2—, —NH—C(═O)—, —C(═O)—NH—, —NR— (wherein R is hydrogen, alkyl or aryl), —C═C—, carbon-carbon triple bond, phenylene (e.g. 1,4-phenylene) and cyclohexylene (e.g. 1,4-cyclohexylene). In certain of these embodiments, the compounds are transcription factor modulators.
In certain embodiments, L1 is —(CH2)n—, where n is 4, 5, 6, 7, or 8.
In certain embodiments, —X1-L1-X2— is —NHC(═O)-L1-C(═O)NH—.
In certain embodiments, —X1-L1-X2— is —C(═O)—NH-L1-C(═O)NH—.
In certain embodiments, A ring is a phenyl ring, and B ring is a pyridyl ring or N-alkylated pyridyl ring.
In certain embodiments, both A and B rings are phenyl rings.
In certain embodiments, A ring is a pyridyl ring, and B ring is a phenyl ring or N-alkylated pyridyl ring.
In certain embodiments, both A and B rings are pyridyl rings.
In certain embodiments, A ring is an N-alkylated pyridyl ring, and B ring is a phenyl ring or pyridyl ring.
In certain embodiments, both A and B rings are N-alkylated pyridyl rings.
In certain embodiments, R4 and/or R5 are/is haloalkyl (e.g. trifluoromethyl).
In certain embodiments, R4 and/or R5 are/is halogen (e.g. Br).
In certain embodiments, one of R4 and R5 is haloalkyl (e.g. trifluoromethyl), and the other is halogen (e.g. Br).
In another embodiment, the compounds disclosed herein comprise a structure of Structure II:
including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, wherein R1-R5, X1, X2, and L1 are defined the same as above. In certain of these embodiments, the compounds are transcription factor modulators.
In certain embodiments, R4 and/or R5 are/is haloalkyl (e.g. trifluoromethyl).
In certain embodiments, R4 and/or R5 are/is halogen (e.g. Br).
In certain embodiments, L1 is —(CH2)n—, where n is 4, 5, 6, 7, or 8.
In certain embodiments, —X1-L1-X2— is —NHC(═O)-L1-C(═O)NH—.
In certain embodiments, —X1-L1-X2— is —C(═O)—NH-L1-C(═O)NH—.
In another embodiment, the compounds disclosed herein comprise a structure selected from the group consisting of Structures IIIA-IIIC:
including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, wherein:
A ring, R1-R5, X1, X2, and L1 are defined the same as above; and
R7 is alkyl group having 1-3 carbon atoms (e.g. methyl). In certain of these embodiments, the compounds are transcription factor modulators.
In certain embodiments, the N-alkylated pyridine ring of Structures IIIA-IIIC may be positively charged and form a salt with one or more suitable counterions (e.g., without limitations, anions derived from pharmaceutically acceptable acids described herein, e.g. acetate, fluoroacetate or other carboxylate).
In certain embodiments, R4 and/or R5 are/is haloalkyl (e.g. trifluoromethyl).
In certain embodiments, R4 and/or R5 are/is halogen (e.g. Br).
In certain embodiments, one of R4 and R5 is haloalkyl (e.g. trifluoromethyl), and the other is halogen (e.g. Br).
In certain embodiments, A ring is a phenyl ring.
In certain embodiments, A ring is a pyridyl ring.
In certain embodiments, A ring is an N-alkylated pyridyl ring.
In certain embodiments, L1 is —(CH2)n—, where n is 4, 5, 6, 7, or 8.
In certain embodiments, —X1-L1-X2— is —NHC(═O)-L1-C(═O)NH—.
In certain embodiments, —X1-L1-X2— is —C(═O)—NH-L1-C(═O)NH—.
In another embodiment, the one or more compounds disclosed herein comprise a structure selected from the group consisting of Structures IVA-IVD:
including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, wherein:
B ring, R1-R5, X1, X2, and L1 are defined the same as above; and
R6 is alkyl group having 1-3 carbon atoms (e.g. methyl). In certain of these embodiments, the compounds are transcription factor modulators.
In certain embodiments, the N-alkylated pyridine ring of Structures IVA-IVD may be positively charged and form a salt with one or more suitable counterions (e.g., without limitations, anions derived from pharmaceutically acceptable acids described herein, acetate, fluoroacetate or other carboxylate).
In certain embodiments, R4 and/or R5 are/is haloalkyl (e.g. trifluoromethyl).
In certain embodiments, R4 and/or R5 are/is halogen (e.g. Br).
In certain embodiments, one of R4 and R5 is haloalkyl (e.g. trifluoromethyl), and the other is halogen (e.g. Br).
In certain embodiments, B ring is a phenyl ring.
In certain embodiments, B ring is a pyridyl ring.
In certain embodiments, B ring is an N-alkylated pyridyl ring.
In certain embodiments, L1 is —(CH2)n—, where n is 4, 5, 6, 7, or 8.
In certain embodiments, —X1-L1-X2— is —NHC(═O)-L1-C(═O)NH—.
In certain embodiments, —X1-L1-X2— is —C(═O)—NH-L1-C(═O)NH—.
In another embodiment, the compounds disclosed herein comprise a structure selected from the group consisting of Structures VA-VE:
including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, wherein A ring, B ring, R1-R7, X1, X2, and L1 are defined the same as above. In certain of these embodiments, the compounds are transcription factor modulators.
In certain embodiments, the N-alkylated pyridine ring of Structures VA-VE may be positively charged and form a salt with one or more suitable counterions (e.g., without limitations, anions derived from pharmaceutically acceptable acids described herein, e.g. acetate, fluoroacetate or other carboxylate).
In certain embodiments, L1 is —(CH2)n—, where n is 4, 5, 6, 7, or 8.
In certain embodiments, —X1-L1-X2— is —NHC(═O)-L1-C(═O)NH—.
In certain embodiments, —X1-L1-X2— is —C(═O)—NH-L1-C(═O)NH—.
In another embodiment, the compounds disclosed herein comprise a structure of Structure VI:
including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, wherein n, X1, and X2 are defined the same as above.
In certain embodiments, n is 4, 5, 6, 7, or 8.
In certain embodiments, —X1—(CH2)n—X2— is —NHC(═O)—(CH2)n—C(═O)NH—.
In certain embodiments, —X1—(CH2)n—X2— is —C(═O)—NH— (CH2)n—C(═O)NH—.
In another embodiment, the compounds disclosed herein comprise a structure selected from the group consisting of Structures VIIA-VIIE:
including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, wherein A ring, B ring, R1-R7, X1, X2, and L1 are defined the same as above. In certain of these embodiments, the compounds are transcription factor modulators.
In certain embodiments, the N-alkylated pyridine ring of Structures VIIA-VIIE may be positively charged and form a salt with one or more suitable counterions (e.g., without limitations, anions derived from pharmaceutically acceptable acids described herein, e.g. acetate, fluoroacetate or other carboxylate).
In certain embodiments, L1 is —(CH2)n—, where n is 4, 5, 6, 7, or 8.
In certain embodiments, —X1-L1-X2— is —NHC(═O)-L1-C(═O)NH—.
In certain embodiments, —X1-L1-X2— is —C(═O)—NH-L1-C(═O)NH—.
In another embodiment, the compounds disclosed herein comprise a structure of Structure VIII:
including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, wherein n, X1, and X2 are defined the same as above. In certain of these embodiments, the compounds are transcription factor modulators.
In certain embodiments, n is 4, 5, 6, 7, or 8.
In certain embodiments, —X1—(CH2)n—X2— is —NHC(═O)—(CH2)n—C(═O)NH—.
In certain embodiments, —X1—(CH2)n—X2— is —C(═O)—NH— (CH2)n—C(═O)NH—.
As used herein, the term “alkyl” refers to a straight or branched chain hydrocarbon having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. Optionally, an alkyl group may contain one or more unsaturated bonds (e.g. —C═C—, and carbon-carbon triple bond).
As used herein, the term “cycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring having from three to seven carbon atoms and which optionally includes an alkyl linker through which it may be attached, preferably a C1-C6 alkyl linker as defined above. Such a ring may be optionally fused to one or more cycloalkyl ring(s), aryl ring(s), and/or heteroaryl ring(s). Exemplary “cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
As used herein, the term “heterocyclic” or the term “heterocyclyl” refers to a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12-membered cycloalkyl ring containing one or more heteroatomic substitutions on the ring selected from S, O or N. Such a ring may be optionally fused to one or more cycloalkyl ring(s), heterocyclic ring(s), aryl ring(s), and/or heteroaryl ring(s). Examples of “heterocyclic” moieties include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, pyrrolidine, piperidine, morpholine, tetrahydrothiopyran, tetrahydrothiophene, piperazine, and the like.
As used herein, the term “aryl” refers to an aromatic cyclic hydrocarbon ring (such as phenyl ring) and which optionally includes an alkyl linker through which it may be attached, preferably a C1-C6 alkyl linker as defined above. Such a ring may be optionally fused to one or more other aryl ring(s). Examples of “aryl” groups include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, biphenyl, imidazolyl as well as substituted derivatives thereof.
As used herein, the term “heteroaryl” refers to an aromatic cyclic hydrocarbon ring containing one or more heteroatomic substitutions on the ring selected from S, O or N, and which optionally includes an alkyl linker through which it may be attached, preferably a C1-C6 alkyl linker as defined above. Such a ring may be optionally fused to one or more other aryl ring(s) and/or heteroaryl ring(s). Examples of “heteroaryl” groups used herein include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuranyl, benzopyrrolyl, benzothiophenyl, indolyl, indazolyl, and substituted derivatives thereof.
As used herein, the term “halogen” or “halo” refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
As used herein, the term “alkoxy” refers to an alkyl group wherein one or more hydrogen and/or carbon atoms are substituted with oxygen or hydroxyl group.
As used herein, the term “aryloxy” refers to an aryl group wherein one or more hydrogen atoms are substituted with oxygen or hydroxyl group.
As used herein, the term “alkylamino” refers to an alkyl group wherein one or more hydrogen and/or carbon atoms are substituted with nitrogen or amino group.
As used herein, the term “arylamino” refers to an amino group substituted with at least an aryl or heteroaryl group on nitrogen. In certain embodiments, the nitrogen is further substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl.
As used herein, the term “haloalkyl” refers to an alkyl group wherein one or more hydrogen and/or carbon atoms are substituted with halogen atom.
As used herein, the term “alkylcarbonyl” refers to R′—C(═O)—, wherein R′ is an optionally substituted alkyl group.
As used herein, the term “arylcarbonyl” refers to R—C(═O)—, wherein R is an optionally substituted aryl group.
As used herein, the term “substituted” refers to substitution(s) on one or more atoms, wherein each atom may be substituted with one or more substituents described above. Further examples of substitutions include, without limitation, halogen, alkyl, alkoxy, alkylamino, haloalkyl, —CN, and alkylcarbonyl.
Unless otherwise specified, all substituents intend to include optionally substituted substituents, i.e. further substituted or not. For example, an alkyl group may be an unsubstituted alkyl group, or a substituted alkyl group as defined supra.
As used herein, a compound or a composition that is “pharmaceutically acceptable” is suitable for use in contact with the tissue or organ of a biological subject without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. If said compound or composition is to be used with other ingredients, said compound or composition is also compatible with said other ingredients.
As used herein, the term “solvate” refers to a complex of variable stoichiometry formed by a solute (e.g., compounds disclosed herein) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, aqueous solution (e.g. buffer), methanol, ethanol and acetic acid. Preferably, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, aqueous solution (e.g. buffer), ethanol and acetic acid. Most preferably, the solvent used is water or aqueous solution (e.g. buffer). Examples for suitable solvates are the mono- or dihydrates or alcoholates of the compound according to the invention.
As used herein, pharmaceutically acceptable salts of a compound refers to any pharmaceutically acceptable acid and/or base additive salt of the compound (e.g., compounds disclosed herein). Suitable acids include organic and inorganic acids. Suitable bases include organic and inorganic bases. Examples of suitable inorganic acids include, but are not limited to: hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid. Examples of suitable organic acids include but are not limited to: acetic acid, trifluoroacetic acid, formic acid, oxalic acid, malonic acid, succinic acid, tartaric acid, maleic acid, fumaric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid, glycolic acid, lactic acid, citric acid and mandelic acid. Examples of suitable inorganic bases include, but are not limited to: ammonia, hydroxyethylamine and hydrazine. Examples of suitable organic bases include, but are not limited to, methylamine, ethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine. The invention further provides for the hydrates and polymorphs of all of the compounds described herein.
II. Compositions
The compounds disclosed herein may contain one or more chiral atoms, or may otherwise be capable of existing as two or more stereoisomers, which are usually enantiomers and/or diastereomers. Accordingly, compositions comprising the compounds disclosed herein may include mixtures of stereoisomers or mixtures of enantiomers, as well as purified stereoisomers, purified enantiomers, stereoisomerically enriched mixtures, or enantiomerically enriched mixtures. The composition provided herein also include the individual isomers of the compound represented by the structures described above as well as any wholly or partially equilibrated mixtures thereof. The compositions disclosed herein also cover the individual isomers of the compound represented by the structures described above as mixtures with isomers thereof in which one or more chiral centers are inverted. Also, it is understood that all tautomers and mixtures of tautomers of the structures described above are included within the scope of the structures and preferably the structures corresponding thereto.
Racemates obtained can be resolved into the isomers mechanically or chemically by methods known per se. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids, such as camphorsulfonic acid. Also advantageous is enantiomer resolution with the aid of a column filled with an optically active resolving agent. The diastereomer resolution can also be carried out by standard purification processes, such as, for example, chromatography or fractional crystallization.
It is also possible to obtain optically active compounds comprising the structure of the transcription factor modulators disclosed herein by the methods described above by using starting materials which are already optically active.
III. Pharmaceutical Formulations
As used herein, a pharmaceutical formulation comprises a therapeutically effective amount of one or more of the compounds or compositions thereof disclosed herein. In certain embodiments, the pharmaceutical formulation further comprises a pharmaceutically acceptable carrier.
As used herein, a “therapeutically effective amount,” “therapeutically effective concentration” or “therapeutically effective dose” is an amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
This amount will vary depending upon a variety of factors, including but not limited to the characteristics of the compounds, compositions, or pharmaceutical formulations thereof (including activity, pharmacokinetics, pharmacodynamics, and bioavailability thereof), the physiological condition of the subject treated (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication) or cells, the nature of the pharmaceutically acceptable carrier or carriers in the formulation, and the route of administration. Further, an effective or therapeutically effective amount may vary depending on whether the compound, composition, or pharmaceutical formulation thereof is administered alone or in combination with other drug(s), other therapy/therapies or other therapeutic method(s) or modality/modalities. One skilled in the clinical and pharmacological arts will be able to determine an effective amount or therapeutically effective amount through routine experimentation, namely by monitoring a cell's or subject's response to administration of the one or more compounds, compositions, or pharmaceutical formulations thereof and adjusting the dosage accordingly. A typical dosage may range from about 0.1 mg/kg to about 100 mg/kg or more, depending on the factors mentioned above. In other embodiments, the dosage may range from about 0.1 mg/kg to about 100 mg/kg; or about 1 mg/kg to about 100 mg/kg; or about 5 mg/kg up to about 100 mg/kg. For additional guidance, see Remington: The Science and Practice of Pharmacy, 21st Edition, Univ. of Sciences in Philadelphia (USIP), Lippincott Williams & Wilkins, Philadelphia, Pa., 2005, which is hereby incorporated by reference as if fully set forth herein for additional guidance for determining a therapeutically effective amount.
As used herein, the term “about” refers to ±10%, ±5%, or ±1%, of the value following “about.”
A “pharmaceutically acceptable carrier” is a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting an active ingredient from one location, body fluid, tissue, organ (interior or exterior), or portion of the body, to another location, body fluid, tissue, organ, or portion of the body. Each carrier is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients, e.g., the transcription factor modulators described herein or other ingredients, of the formulation and suitable for use in contact with the tissue or organ of a biological subject without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable carriers are well known in the art and include, without limitation, (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) alcohol, such as ethyl alcohol and propane alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
The pharmaceutical formulations disclosed herein may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
The concentration of the one or more compounds disclosed herein in a pharmaceutical formulation can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the biological subject's needs. For example, the concentration of the compounds disclosed herein can be about 0.0001% to about 100%, about 0.001% to about 50%, about 0.01% to about 30%, about 0.1% to about 20%, about 1% to about 10% wt.
A suitable pharmaceutically acceptable carrier may be selected taking into account the chosen mode of administration, and the physical and chemical properties of the compounds.
One skilled in the art will recognize that a pharmaceutical formulation containing the one or more compounds disclosed herein or compositions thereof can be administered to a subject by various routes including, without limitation, orally or parenterally, such as intravenously. The composition may also be administered through subcutaneous injection, subcutaneous embedding, intragastric, topical, and/or vaginal administration. The composition may also be administered by injection or intubation.
In one embodiment, the pharmaceutical carrier may be a liquid and the pharmaceutical formulation would be in the form of a solution. In another embodiment, the pharmaceutically acceptable carrier is a solid and the pharmaceutical formulation is in the form of a powder, tablet, pill, or capsules. In another embodiment, the pharmaceutical carrier is a gel and the pharmaceutical formulation is in the form of a suppository or cream.
A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or table-disintegrating agents, it can also be an encapsulating material. In powders, the carrier is a finely divided solid that is in admixture with the finely divided active ingredient. In tablets, the active-ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to about 99% of the one or more transcription factor modulators disclosed herein. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Besides containing an effective amount of the one or more compounds described herein or compositions thereof, the pharmaceutical formulations provided herein may also include suitable diluents, preservatives, solubilizers, emulsifiers, adjuvant and/or carriers.
The pharmaceutical formulation can be administered in the form of a sterile solution or suspension containing other solutes or suspending agents, for example, enough saline or glucose to make the solution isotonic, bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
Additional pharmaceutical formulations will be evident to those skilled in the art, including formulations involving binding agent molecules in sustained- or controlled-delivery formulations. Techniques for formulating a variety of other sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. See, for example, PCT/US93/0082948 which is incorporated herein by reference as if fully set forth herein for the techniques of controlled release of porous polymeric microparticles for the delivery of pharmaceutical formulations. Additional examples of sustained-release preparations include semipermeable polymer matrices in the form of shaped articles, e.g. films, or microcapsules. Sustained release matrices may include polyesters, hydrogels, polylactides, copolymers of L-glutamic acid and gamma ethyl-L-glutamate, poly (2-hydroxyethyl-methacrylate), ethylene vinyl acetate or poly-D (−)-3-hydroxybutyric acid. Sustained-release compositions also include liposomes, which can be prepared by any of several methods known in the art.
IV. Methods of Treatment
One aspect of the present disclosure relates to methods of treating a cancer or a tumor in a subject comprising administering to the subject a therapeutically effective amount of one or more compounds, compositions, or pharmaceutical formulations disclosed herein.
Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound, composition, or formulation being used, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated, include, without limitation, subject age, weight, gender, diet, time of administration, time and frequency of administration, drug combination(s), reaction sensitivities, and response to therapy. Administration of the compound, composition, or pharmaceutical formulation may be effected continuously or intermittently. In any treatment regimen, the compound, composition, or pharmaceutical formulation may be administered to a subject either singly or in a cocktail containing two or more compounds or compositions thereof, other therapeutic agents, compositions, or the like, including, but not limited to, tolerance-inducing agents, potentiators and side-effect relieving agents. All of these agents are administered in generally-accepted efficacious dose ranges such as those disclosed in the Physician's Desk Reference, 41st Ed., Publisher Edward R. Barnhart, N.J. (1987), which is herein incorporated by reference as if fully set forth herein. In certain embodiments, an appropriate dosage level will generally be about 0.001 to about 50 mg per kg subject body weight per day that can be administered in single or multiple doses. Preferably, the dosage level will be about 0.005 to about 25 mg/kg, per day; more preferably about 0.01 to about 10 mg/kg per day; and even more preferably about 0.05 to about 1 mg/kg per day. In some embodiments, the daily dosage may be between about 10−6 g/kg to about 5 g/kg of body weight.
“Treating” or “treatment” of a condition may refer to preventing the condition, slowing the onset or rate of development of the condition, reducing the risk of developing the condition, preventing or delaying the development of symptoms associated with the condition, reducing or ending symptoms associated with the condition, generating a complete or partial regression of the condition, or some combination thereof. With regard to cancer specifically, “treating” or “treatment” may refer to reducing the size or number of tumors, slowing or preventing tumor growth, reducing or preventing malignancy of a tumor, lowering a tumor grade or preventing an increase in tumor grade.
In some embodiments, the one or more compounds disclosed herein or compositions or pharmaceutical formulations thereof may be administered in combination with one or more additional therapeutic agents for the treatment of cancer. “In combination” or “in combination with,” as used herein, means in the course of treating the same cancer in the same subject using two or more agents, drugs, treatment regimens, treatment modalities or a combination thereof, in any order. This includes simultaneous administration (in the same or separate formulations), as well as administration in a temporally spaced order of up to several days apart. Such combination treatment may also include more than a single administration of any one or more of the agents, drugs, treatment regimens or treatment modalities. Further, the administration of the two or more agents, drugs, treatment regimens, treatment modalities or a combination thereof may be by the same or different routes of administration.
Examples of therapeutic agents that may be administered in combination with the compounds disclosed herein or compositions or pharmaceutical formulations thereof include, but are not limited to, anti-cancer agents and radioisotopes. The therapeutic agent may also include a metal, metal alloy, intermetallic or core-shell nanoparticle bound to a chelator that acts as a radiosensitizer to render the targeted cells more sensitive to radiation therapy as compared to healthy cells.
In one embodiment, the therapeutic agent is an anti-cancer agent. Anti-cancer agents that may be used in accordance with certain embodiments described herein are often cytotoxic or cytostatic in nature and may include, but are not limited to, alkylating agents; antimetabolites; anti-tumor antibiotics; topoisomerase inhibitors; mitotic inhibitors; hormones (e.g., corticosteroids); targeted therapeutics (e.g., selective estrogen receptor modulators (SERMs)); toxins; immune adjuvants, immunomodulators, and other immunotherapeutics (e.g., therapeutic antibodies and fragments thereof, recombinant cytokines and immunostimulatory molecules—synthetic or from whole microbes or microbial components); enzymes (e.g., enzymes to cleave prodrugs to a cytotoxic agent at the site of the tumor); nucleases; antisense oligonucleotides; nucleic acid molecules (e.g., mRNA molecules, cDNA molecules or RNAi molecules such as siRNA or shRNA); chelators; boron compounds; photoactive agents and dyes. Examples of anti-cancer agents that may be used as therapeutic agents in accordance with certain embodiments of the disclosure include, but are not limited to, 13-cis-retinoic acid, 2-chlorodeoxyadenosine, 5-azacitidine, 5-fluorouracil, 6-mercaptopurine, 6-thioguanine, actinomycin-D, adriamycin, aldesleukin, alitretinoin, all-transretinoic acid, alpha interferon, altretamine, amethopterin, amifostine, anagrelide, anastrozole, arabinosylcytosine, arsenic trioxide, amsacrine, aminocamptothecin, aminoglutethimide, asparaginase, azacytidine, bacillus calmette-guerin (BCG), bendamustine, bexarotene, bicalutamide, bortezomib, bleomycin, busulfan, calcium leucovorin, citrovorum factor, capecitabine, canertinib, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, cortisone, cyclophosphamide, cytarabine, darbepoetin alfa, dasatinib, daunomycin, decitabine, denileukin diftitox, dexamethasone, dexasone, dexrazoxane, dactinomycin, daunorubicin, decarbazine, docetaxel, doxorubicin, doxifluridine, eniluracil, epirubicin, epoetin alfa, erlotinib, everolimus, exemestane, estramustine, etoposide, filgrastim, fluoxymesterone, fulvestrant, flavopiridol, floxuridine, fludarabine, fluorouracil, flutamide, gefitinib, gemcitabine, ozogamicin, goserelin, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, hexamethylmelamine, hydrocortisone hydroxyurea, interferon alpha, interleukin-2, interleukin-11, isotretinoin, ixabepilone, idarubicin, imatinib mesylate, ifosfamide, irinotecan, lapatinib, lenalidomide, letrozole, leucovorin, leuprolide, liposomal Ara-C, lomustine, mechlorethamine, megestrol, melphalan, mercaptopurine, mesna, methotrexate, methylprednisolone, mitomycin C, mitotane, mitoxantrone, nelarabine, nilutamide, octreotide, oprelvekin, oxaliplatin, paclitaxel, pamidronate, pemetrexed, PEG Interferon, pegaspargase, pegfilgrastim, PEG-L-asparaginase, pentostatin, plicamycin, prednisolone, prednisone, procarbazine, raloxifene, romiplostim, ralitrexed, sapacitabine, sargramostim, satraplatin, sorafenib, sunitinib, semustine, streptozocin, tamoxifen, tegafur, tegafur-uracil, temsirolimus, temozolamide, teniposide, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tretinoin, trimitrexate, alrubicin, vincristine, vinblastine, vindestine, vinorelbine, vorinostat, and zoledronic acid.
Therapeutic antibodies and functional fragments thereof, that may be used as anti-cancer agents in accordance with certain embodiments of the disclosure include, but are not limited to, alemtuzumab, bevacizumab, cetuximab, edrecolomab, gemtuzumab, ibritumomab tiuxetan, panitumumab, rituximab, tositumomab, and trastuzumab and other antibodies associated with specific diseases listed herein.
Toxins that may be used as anti-cancer agents in accordance with certain embodiments of the disclosure include, but are not limited to, ricin, abrin, ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, and Pseudomonas endotoxin.
Radioisotopes that may be used as therapeutic agents in accordance with certain embodiments of the disclosure include, but are not limited to, 32P, 89Sr, 90Y, 99mTc, 99Mo, 131I, 153Sm, 177Lu, 186Re, 213B, 223Rd and 225AC.
The frequency of dosing will depend upon the pharmacokinetic parameters of the therapeutic agents in the pharmaceutical formulation (e.g. the one or more compounds disclosed herein) used. Typically, a pharmaceutical formulation is administered until a dosage is reached that achieves the desired effect. The formulation may therefore be administered as a single dose, or as multiple doses (at the same or different concentrations/dosages) over time, or as a continuous infusion. Further refinement of the appropriate dosage is routinely made. Appropriate dosages may be ascertained through use of appropriate dose-response data. Long-acting pharmaceutical formulations may be administered every 3 to 4 days, every week, or biweekly depending on the half-life and clearance rate of the particular formulation.
In certain embodiments, the one or more compounds disclosed herein or compositions or pharmaceutical formulations thereof may be administered in combination with a therapeutic agent or radiotherapy. In some embodiments, the one or more compounds or compositions or pharmaceutical formulations thereof may be used in combination with imatinib (Gleevec), and in certain cancers being treated. In some of these embodiments the cancer being treated is leukemia. In certain embodiments, the type of leukemia may include, but is not limited to, acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), CML (imitinib resistant), multiple myeloma, B-cell myelomonocytic leukemia, T-cell myelomonocytic leukemia, biphenotypic B-cell leukemia, and/or lymphoma. In certain of these embodiments, the type of leukemia may be treatable by a compound disclosed herein, including but not limited to YT30.
In certain embodiments, the cancer is breast cancer, central nervous system cancer, colon cancer, prostate cancer, lung cancer, leukemia, renal cancer, ovarian cancer, melanoma, liver cancer, and/or cervical cancer.
In certain embodiments, the cancer is leukemia. In certain of these embodiments, the type of leukemia may include, but is not limited to, acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), CML (imitinib resistant), multiple myeloma, B-cell myelomonocytic leukemia, T-cell myelomonocytic leukemia, biphenotypic B-cell leukemia, and/or lymphoma. In certain embodiments, the ALL is T-cell ALL and/or B-cell ALL. In certain embodiments, the leukemia may be treatable by one or more compounds selected from the group consisting of YT29, YT30, YT45, YT46, YT51, YT53, YT54, YT58, YT61˜YT63, YT65, YT67, YT68, YT73, YT74, YT76˜YT80, YT86, YT88, YT91, YT99, YT108˜YT110, YT116˜YT118, YT121˜YT123, YT127, YT128, YT131, YT132, and YT134˜YT139. In certain embodiments, the leukemia may be treatable by one or more compounds comprising a structure selected from the group consisting of Formula I, Formula II, Formula V, Formula VI, Formula VII, Structure I, Structure II, Structure IIIA, Structure IIIB, Structure IIIC, Structure IVA, Structure IVB, Structure IVC, Structure IVD, Structure VA, Structure VB, Structure VC, Structure VD, Structure VE, Structure VI, Structure VIIA, Structure VIIB, Structure VIIC, Structure VIID, Structure VIIE, and Structure VIII. In certain of these embodiments, the leukemia is ALL.
In certain embodiments, the cancer is breast cancer. In certain of these embodiments, the type of breast cancer may be metastatic adenocarcinoma, infiltrating ductal carcinoma, papillary infiltrating ductal carcinoma, and/or metastatic mammary gland carcinosarcoma. In certain embodiments, the breast cancer may be treatable by one or more compounds selected from the group consisting of YT30, YT86, YT88, and YT128. In certain embodiments, the breast cancer may be treatable by one or more compounds comprising a structure selected from the group consisting of Formula I, Formula VI, Formula VII, Structure I, Structure II, Structure IIIA, Structure IIIB, Structure IIIC, Structure IVA, Structure IVB, Structure IVC, Structure IVD, Structure VA, Structure VB, Structure VC, Structure VD, Structure VE, and Structure VI.
In certain embodiments, the cancer is central nervous system cancer. In certain of these embodiments, the type of central nervous system cancer is glioblastoma, astrocytoma, and/or glial cell neoplasm. In certain embodiments, the central nervous system cancer may be treatable by one or more compounds selected from the group consisting of YT30, YT86, YT88, and YT128. In certain embodiments, the central nervous system cancer may be treatable by one or more compounds comprising a structure selected from the group consisting of Formula I, Formula VI, Formula VII, Structure I, Structure II, Structure IIIA, Structure IIIB, Structure IIIC, Structure IVA, Structure IVB, Structure IVC, Structure IVD, Structure VA, Structure VB, Structure VC, Structure VD, Structure VE, and Structure VI.
In certain embodiments, the cancer is colon cancer. In certain of these embodiments, the colon cancer may be treatable by a compound including, but not limited to, YT30. In certain of these embodiments, the colon cancer may be treatable by one or more compounds comprising a structure selected from the group consisting of Formula I, Structure I, Structure II, Structure IIIA, Structure IIIB, Structure IIIC, Structure IVA, Structure IVB, Structure IVC, Structure IVD, Structure VA, Structure VB, Structure VC, Structure VD, Structure VE, and Structure VI.
In certain embodiments, the cancer is cervical cancer. In certain of these embodiments, the type of cervical cancer may be positive for human papilloma virus (HPV) 16 and/or HPV 18. In certain of these embodiments, the cervical cancer may be treatable by one or more compounds selected from the group consisting of YT30, YT86, YT88, and YT128. In certain embodiments, the cervical cancer may be treatable by one or more compounds comprising a structure selected from the group consisting of Formula I, Formula VI, Formula VII, Structure I, Structure II, Structure IIIA, Structure IIIB, Structure IIIC, Structure IVA, Structure IVB, Structure IVC, Structure IVD, Structure VA, Structure VB, Structure VC, Structure VD, Structure VE, and Structure VI.
In certain embodiments, the cancer is ovarian cancer. In certain of these embodiments, the ovarian cancer may be treatable by one or more compounds selected from the group consisting of YT30, YT86, YT88, and YT128. In certain embodiments, the ovarian cancer may be treatable by one or more compounds comprising a structure selected from the group consisting of Formula I, Formula VI, Formula VII, Structure I, Structure II, Structure IIIA, Structure IIIB, Structure IIIC, Structure IVA, Structure IVB, Structure IVC, Structure IVD, Structure VA, Structure VB, Structure VC, Structure VD, Structure VE, and Structure VI.
In certain embodiments, the cancer is prostate cancer. In certain of these embodiments, the prostate cancer may be treatable by one or more compounds selected from the group consisting of YT30 and YT88. In certain embodiments, the prostate cancer may be treatable by one or more compounds comprising a structure selected from the group consisting of Formula I, Formula VI, Structure I, Structure II, Structure IIIA, Structure IIIB, Structure IIIC, Structure IVA, Structure IVB, Structure IVC, Structure IVD, Structure VA, Structure VB, Structure VC, Structure VD, Structure VE, and Structure VI.
In certain embodiments, the cancer is renal cancer. In certain of these embodiments, the renal cancer may be clear cell carcinoma metastasis, renal cell carcinoma, renal spindle cell carcinoma and/or hypernephroma. In certain embodiments, the renal cancer may be treatable by one or more compounds selected from the group consisting of YT30, YT86, YT88, and YT128. In certain embodiments, the renal cancer may be treatable by one or more compounds comprising a structure selected from the group consisting of Formula I, Formula VI, Formula VII, Structure I, Structure II, Structure IIIA, Structure IIIB, Structure IIIC, Structure IVA, Structure IVB, Structure IVC, Structure IVD, Structure VA, Structure VB, Structure VC, Structure VD, Structure VE, and Structure VI.
In certain embodiments, the cancer is lung cancer. In certain of these embodiments, the lung cancer may be non-small cell lung cancer (NSCLC), large cell carcinoma, squamous cell carcinoma, and/or adenocarcinoma. In certain embodiments, the lung cancer may be treatable by one or more compounds selected from the group consisting of YT30, YT86, and YT128. In certain embodiments, the lung cancer may be treatable by one or more compounds comprising a structure selected from the group consisting of Formula I, Formula VI, Formula VII, Structure I, Structure II, Structure IIIA, Structure IIIB, Structure IIIC, Structure IVA, Structure IVB, Structure IVC, Structure IVD, Structure VA, Structure VB, Structure VC, Structure VD, Structure VE, and Structure VI.
In certain embodiments, the cancer is melanoma. In certain of these embodiments, the type of melanoma may be malignant amelanotic melanoma and/or melanotic melanoma. In certain embodiments, the melanoma may be treatable by a transcription factor modulator including, but not limited to, YT30. In certain embodiments, when the cancer is melanoma, the melanoma may be treatable by one or more transcription factor modulators comprising a structure selected from the group consisting of Formula I, Structure I, Structure II, Structure IIIA, Structure IIIB, Structure IIIC, Structure IVA, Structure IVB, Structure IVC, Structure IVD, Structure VA, Structure VB, Structure VC, Structure VD, Structure VE, and Structure VI.
In some embodiments, specific compounds disclosed herein may be preferred for the treatment of specific cancer types. Table 6 provides a non-limiting list of specific cancer types that can be treated by specific compounds provided herein. In other embodiments, the cancer types listed in Table 6 may be treatable by one or more compounds other than those listed in the table, and one or more compounds listed in Table 6 may be used to treat types of cancer other than those listed.
Another aspect of the present disclosure relates to the use of one or more compounds disclosed herein or compositions or pharmaceutical formulations thereof in the manufacture of a medicament for the treatment of cancer. For this aspect, the compounds, compositions, and formulations are the same as disclosed above, and the treatment of cancer is the same as described supra.
Another aspect described herein relates to a method of treating a condition regulatable by a transcription factor and/or cofactor comprising administering to the subject a therapeutically effective amount of one or more compounds disclosed herein or compositions or pharmaceutical formulations thereof. In some embodiments, the condition is a disease related to dysfunction of a transcription factor and/or cofactor. In certain of these embodiments, the compounds provided herein are transcription factor modulators. In certain embodiments, the transcription factor is selected from the group consisting of forkhead box protein P3 (FOXP3) and myocyte enhancer factor 2 (MEF2). In certain embodiments, the transcription factor modulators binds to a highly conserved hydrophobic groove on the MADS-box of MEF2. In certain embodiments, the condition is a cancer as described above, and the suitable compounds, compositions, or pharmaceutical formulations are the same as disclosed herein.
In certain embodiments where the compounds provided herein are transcription factor modulators, the compounds may selectively bind a transcription factor or cofactor.
In certain embodiments where the compounds provided herein are transcription factor modulators, the compounds may modulate the function of transcription factors that are associated with certain diseases. In certain embodiments, the diseases are cancers as described herein.
In certain embodiments where the compounds provided herein are transcription factor modulators, the compounds may directly bind the transcription factor and modulate its interaction with transcription cofactors such as transcription co-activators and co-repressors. In certain embodiments, the transcription cofactor is selected from the group consisting of calcineurin binding protein 1, histone deacetylases (HDACs), E1A binding protein P300, CREB binding protein, extracellular signal-regulated kinase 5, myoblast differentiation protein, Smad protein, nuclear factor of activated T cell, myocardin, and positive transcription elongation factor b. In some embodiments, the transcription cofactor is a Class IIa HDAC.
Another aspect of the present disclosure relates to the use of one or more compounds disclosed herein or compositions or pharmaceutical formulations thereof in the manufacture of a medicament for the treatment of a condition regulatable by a transcription factor and/or cofactor. For this aspect, the one or more compounds or compositions or pharmaceutical formulations thereof, the transcription factors and/or cofactors, and the conditions regulatable by the transcription factor and/or cofactor are the same as disclosed above, and the treatment of the condition is the same as described supra.
The following examples are intended to illustrate various embodiments of the invention. As such, the specific embodiments discussed are not to be construed as limitations on the scope of the invention. It will be apparent to one skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of invention, and it is understood that such equivalent embodiments are to be included herein. Further, all references cited in the disclosure are hereby incorporated by reference in their entireties, as if fully set forth herein.
Methods
Treatment of Cells.
Various human leukemia cells were grown to the logarithmic growth phase and seeded into 24-well plates. Plated cells were incubated at 37° C. in a 5% CO2 humidified incubator for 24 hours and treated with various concentrations of YT30 or other compounds disclosed herein. Treated cells were further incubated for 72 hours and then were examined for cell proliferation. Cell proliferation was determined using the CellTiter-Glo Luminescence Cell Viability assay (Promega Corporation, Madison, Wis.) according to the manufacturer's protocol. The calculated inhibition rate was determined with the following formula: Inhibition rate (%)=(1−Luminescence of experimental group/Luminescence of control group)×100. IC50 is the calculated concentration of a compound needed to inhibit half of the maximum cell growth (equivalent to cell growth in control group) based on the corresponding dose-response curve under the described experimental conditions.
Results
YT30 Inhibits Cell Proliferation of Numerous Leukemia Cell Lines.
Table 7 provides the YT30 IC50 (μM) concentrations for inhibiting various leukemia cell lines. YT30 inhibited the proliferation of all leukemia cell lines tested. The strongest YT30 cell growth inhibition was observed in the Jurkat, HL60, RS4, MOLT-4, and SEM leukemia cells under the described experimental conditions.
YT30, YT54, and Other Compounds Inhibited the Growth of the Nalm-6 Leukemia Cell Line.
Table 8 displays the survival percentage of Nalm-6 leukemia cells that were treated with YT30, YT54, and numerous other compounds.
Methods
Inducing B Cell Lymphoblastic Leukemia in BALB/c Nude Mice and Treatment with YT30.
BALB/c nu/nu nude mice were 4 to 5 weeks old with an average weight of 22.4±1.03 grams. The mice were raised under specific pathogen-free (SPF) conditions and had access to food and water freely. Cyclophosphamide at about 130 mg/kg per day was administrated with intraperitoneal (IP) injection for 2 days. Twenty-four hours later, a suspension of 3.5×106 or 5×106 Nalm-6 cells (0.2 mL) were injected through tail vein of each BALB/c nude mouse. Five days later, the mice were randomly divided into a YT30 treated group (n=5) and a solvent control group (n=5).
Mice in the YT30 treated group were intraperitoneally injected with 200 μL of YT30 (50 mg/kg) once a day, for 5 days a week, and for 3 or 4 weeks. The mice in the solvent control group were intraperitoneally injected with the same volume of solvent (20% DMSO, 80% of 20% w/v (2-hydroxypropyl)-β-cyclodextrin in PBS), and were on the same treatment schedule as the YT30 treated group. The body weights of the mice were recorded prior to the start of the treatment and at least twice a week thereafter. The dosages were adjusted according to the body weight to conform to the 50 mg/kg/day treatment plan. Each mouse of every group was also monitored daily for any other symptoms of side effects including change in behavior, activity or posture, areas of redness and swelling, and food and water withdrawal. The mice were euthanized when moribund or if weight loss was more than 20% during the experiment. Dates of death were recorded.
Results
YT30 significantly extended the survival time of BALB/c nude mice with acute lymphoblastic leukemia (Table 9 and
The results demonstrated that YT30 significantly inhibited leukemia progression in Balb/c nude mice. Moreover, the data shows that YT30 treatment at an early stage of leukemia development further increased life span and decreased disease progression even more. All of the data were analyzed with Microsoft Excel or SPSS14.0 statistical software count data using the x±s. The difference between the groups was statistically significant with P<0.05.
YT30 was tested for growth inhibition against 67 human cancer cell lines derived from diverse tissues including the National Cancer Institute human cancer cell lines (NCI-60). These cell lines were grown to the logarithmic growth phase and seeded into 96-well plates. Plated cells were incubated at 37° C. in a 5% CO2 humidified incubator for about 24 hours. Cells in different wells were treated with various concentrations of YT30, YT86, YT88, or YT128. Treated cells were further incubated for 72 hours and then were examined for cell viability. Cell viabilities were determined by the CellTiter-Glo Luminescence Cell Viability assay kit (Promega Corporation, Madison, Wis.) according to manufacturer's protocol. Cell growth inhibition rates were determined by the following formula: Inhibition rate (%)=(1−Luminescence of compound treated group/Luminescence of DMSO control group)×100. IC50 is the calculated concentration of a compound needed to inhibit half of the maximum cell growth (equivalent to cell growth in control group) based on the corresponding dose-response curve under the described experimental conditions.
Results
YT30 growth inhibition was detected in 49 of the 67 human cancer cell lines (Table 10). YT30 inhibited the growth of breast, central nervous system (CNS), colon, prostate, non-small cell lung cancer (NSCLC), leukemia, renal, ovarian, melanoma, liver, and cervical cancer cell lines (Table 10).
Additionally, YT86 and YT128 inhibited the growth of breast, central nervous system (CNS), cervical, lung, leukemia, renal, and ovarian cancer cells (Table 11). YT88 inhibited the growth of breast, central nervous system (CNS), cervical, prostate, leukemia, renal, and ovarian cancer cells (Table 11). All of the various cell lines and their characteristics of which compounds inhibit cell growth are listed in Table 12.
1MT = mutant; WT = wild type
2MDR = Multidrug Resistance (Wu et. al., 1992)
Growth inhibition experiments were performed as previously described. The combination of YT30 and imatinib displayed a synergistic effect in growth inhibition of a Nalm-6, a leukemia cell line. After 72 hrs, combination of YT30 and Imatinib showed an increase in growth inhibition compared to addition of each agent alone (Table 13). For example, 1 μM YT30 alone induced growth inhibition by 8.4%, 10 μM imatinib induced growth inhibition by 44%, but the combination of 1 μM YT30 and 10 μM imatinib induced growth inhibition by 97%. The synergistic effects were also observed when the YT30 and imatinib were combined with other concentrations.
Tumor Transplantation and Treatment of NOD/SCID Mice.
Female Nonobese Diabetic/Severe Combined Immunodeficiency (NOD/SCID) mice that were 4-6 weeks old were used in the experiment. The mice were fed under specific pathogen free (SPF) conditions. Food and water were available to the mice at will. A suspension of 1×107 cells per mouse B-myelomonocytic leukemia MV4-11 cells (0.2 mL) in logarithmic phase were inoculated subcutaneously into the right back of the NOD/SCID nude mice.
The general conditions of the mice and the growth of the transplanted tumor were monitored. When the transplanted tumor grew to about 100 mm3 in size, the NOD/SCID mice were divided into four groups with five mice in each group so that each group of mice had a similar average tumor size. The control group received an intraperitoneal (IP) injection of 0.2 mL of solvent (20% DMSO, 80% of 20% w/v (2-hydroxypropyl)-β-cyclodextrin made in PBS). The imatinib group received gavage of 100 mg/kg/day imatinib. The high dosage group received an intraperitoneal injection of 50 mg/kg/day of YT30 (0.2 mL in volume) suspended in solvent (20% DMSO, 80% of 20% w/v (2-hydroxypropyl)-β-cyclodextrin made in PBS), while the low dosage group received IP injection of 25 mg/kg/day YT30 (0.2 mL in volume). Frequency of the administration was once per day and the experiment lasted 27 days after treatment started.
The body weights of the mice were recorded prior to the start of treatment and twice every week thereafter. Each mouse of every group was monitored daily for any other symptoms of side effects including change in behavior, activity or posture, areas of redness and swelling, and food and water withdrawal. Caliper measurements of the longest perpendicular tumor diameters were performed every 2 days to estimate the tumor volume; the following formula: 4π/3×(width/2)2×(length/2) was used to calculate the three-dimensional volume of an ellipse. The tumor inhibition rate was calculated according to tumor volume: Tumor inhibition rate by size (%)=(Tumor volume of the control group−Tumor volume of the treated group)/Tumor volume of the control group×100. The BALB/c nude mice were euthanized on the next day after the final injection and the subcutaneous tumor nodules were taken out intact and weighed. Tumor inhibition rate by weight (%)=(Tumor weight of the control group−Tumor weight of the treated group)/Tumor weight of the control group×100.
Results
YT30 inhibited the growth of subcutaneously transplanted leukemia tumors in NOD/SCID mice. About one week after seeding the NOD/SCID mice with MV4-11 cells, all of the transplanted tumors grew to a size around 100 mm3. The rate of successful transplantation was 100%. After 27 days of treatment with YT30, tumor growth inhibition by size is 58.8% for the high dosage YT30 treatment group and 38.8% for the low dosage YT30 treatment group (Table 14). The difference in tumor growth inhibitions between the high dosage and the low dosage group demonstrated clear dose-response relationship. The tumor weight was also significantly less than that of the control group, and the difference was statistically significant.
The references, patents and published patent applications listed below, and all references cited in the specification above are hereby incorporated by reference in their entireties, as if fully set forth herein.
This application claims priority to U.S. Provisional Patent Application Ser. No. 61/773,798, filed Mar. 6, 2013, which is incorporated herein by reference in its entirety, as if fully set forth herein.
| Number | Date | Country | |
|---|---|---|---|
| 61773798 | Mar 2013 | US |
