WO2014138507A1 - Treatment of cervical cancer and/or ovarian cancer using a transcription factor modulator - Google Patents

Treatment of cervical cancer and/or ovarian cancer using a transcription factor modulator Download PDF

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Publication number
WO2014138507A1
WO2014138507A1 PCT/US2014/021451 US2014021451W WO2014138507A1 WO 2014138507 A1 WO2014138507 A1 WO 2014138507A1 US 2014021451 W US2014021451 W US 2014021451W WO 2014138507 A1 WO2014138507 A1 WO 2014138507A1
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Prior art keywords
formula
group
cervical cancer
pharmaceutically acceptable
certain embodiments
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PCT/US2014/021451
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French (fr)
Inventor
Lin Chen
Xiaojiang Chen
Meng XIA
Dahai GAI
Guangshi TAO
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C & C Biopharma, Llc
Tianshu Biotechnology, Ltd.
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Priority claimed from PCT/CN2013/072247 external-priority patent/WO2014134800A1/en
Application filed by C & C Biopharma, Llc, Tianshu Biotechnology, Ltd. filed Critical C & C Biopharma, Llc
Publication of WO2014138507A1 publication Critical patent/WO2014138507A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol

Definitions

  • Cervical cancer is the third most common and one of the most deadly cancers affecting women, with an estimated 530,000 new cases and 275,000 deaths each year (Ferlay et. al., 2010). As the world's most populous country, with 70% of its population living in rural areas, China accounts for 14% of the world's annual incidence of cervical cancer (75,500 new cases) and 12% of the world's annual mortality from cervical cancer (34,000 deaths) (Ferlay et. al., 2010). Negative outcomes associated with cervical cancer are largely due to limited accessibility to efficient identification methods at early stages in developing countries and the high tendency of metastasis.
  • Chemotherapy drugs (including cisplatin and carboplatin) generally function 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.
  • Mainstream cytotoxic chemotherapy drugs act in a non-specific manner and kill both tumor and normal cells.
  • chemotherapy drugs may also induce new DNA mutations that may result in the occurrence of new cancer incidences.
  • One aspect of the invention relates to a method of treating cervical cancer and/or ovarian cancer by administering one or more transcription factor modulators disclosed herein, or a pharmaceutical composition thereof.
  • Another aspect of the invention relates to the use of one or more transcription factor modulators disclosed herein, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of cervical cancer and/or ovarian cancer.
  • Figure 1 Dose dependent growth inhibition of HeLa cells by CC54.
  • A Effects of CC54 after treatment of 24 hours;
  • B Effects of CC54 after treatment of 48 hours;
  • C Effects of CC54 after treatment of 72 hours.
  • Figure 2 Dose dependent growth inhibition of CaSki cells by CC54.
  • A Effects of CC54 after treatment of 24 hours;
  • B Effects of CC54 after treatment of 48 hours;
  • C Effects of CC54 after treatment of 72 hours.
  • Figure 3 Dose dependent growth inhibition of L292 cells by CC54 after treatment of 48 hours.
  • FIG. 4 Flow cytometry data showing CC54 induced early (quadrant B1 ) and late (quadrant B4) stage apoptosis in HeLa cervical cancer cells.
  • A Results from control groups (no solvent and DMSO); and
  • B Results from groups treated with various concentrations of CC54 (10 ⁇ 40 ⁇ ).
  • FIG. 5 Flow cytometry data showing CC54 induced early (quadrant B1 ) and late (quadrant B4) stage apoptosis in CaSki cervical cancer cells.
  • A Results from control groups (no solvent and DMSO); and
  • B Results from groups treated with various concentrations of CC54 (10 ⁇ 40 ⁇ ).
  • FIG. 6 Flow cytometry data showing CC54 induced early (quadrant B1 ) and late (quadrant B4) stage apoptosis in C33A cervical cancer cells.
  • A Results from control groups (no solvent and DMSO); and
  • B Results from groups treated with various concentrations of CC54 (10 ⁇ 40 ⁇ ).
  • FIG. 7 Flow cytometry data showing CC54 induced early (quadrant B1 ) and late (quadrant B4) stage apoptosis in SKOV3 ovarian cancer cells.
  • A Results from control groups (no solvent and DMSO); and
  • B Results from groups treated with various concentrations of CC54 (10 ⁇ 40 ⁇ ).
  • Figure 8 Dose dependent growth inhibition of HeLa cells by CC30.
  • A Effects of CC30 after treatment of 24 hours;
  • B Effects of CC30 after treatment of 48 hours;
  • C Effects of CC30 after treatment of 72 hours.
  • Figure 9 Dose dependent growth inhibition of CaSki cells by CC30.
  • A Effects of CC30 after treatment of 24 hours;
  • B Effects of CC30 after treatment of 48 hours;
  • C Effects of CC30 after treatment of 72 hours.
  • Figure 10 Dose dependent growth inhibition of L292 cells by CC30 after treatment of 48 hours.
  • Figure 1 Dose dependent growth inhibition of CaSki, SiHa, HeLa, and C4I cells by CC30.
  • Figure 12 Dose dependent induction of apoptosis in CaSki, SiHa, HeLa, and C4I cells by CC30 observed as an increase in Caspase 3/7 activity.
  • FIG. 13 Hoechest 33258 fluorescence staining of the CaSki cells.
  • A Apoptotic CaSki cells treated with CC30; and
  • B Normal and healthy CaSki cells treated with DMSO.
  • FIG. 14 Flow cytometry data showing CC30 induced early (quadrant B1 ) and late (quadrant B4) stage apoptosis in HeLa cervical cancer cells.
  • A Results from control groups (cell growth media and DMSO); and
  • B Results from groups treated with various concentrations of CC30 (10 ⁇ 40 ⁇ ).
  • FIG. 15 Flow cytometry data showing CC30 induced early (quadrant B1 ) and late (quadrant B4) stage apoptosis in CaSki cervical cancer cells.
  • A Results from control groups (cell growth media and DMSO); and
  • B Results from groups treated with various concentrations of CC30 (10 ⁇ 40 ⁇ ).
  • FIG. 16 Flow cytometry data showing CC30 induced (quadrant B1 ) and late (quadrant B4) stage apoptosis in C33A cervical cancer cells.
  • A Results from control groups (cell growth media and DMSO); and
  • B Results from groups treated with various concentrations of CC30 (10 ⁇ 40 ⁇ ).
  • FIG. 17 Flow cytometry data showing CC30 induced (quadrant B1 ) and late (quadrant B4) stage apoptosis in SKOV3 cervical cancer cells.
  • A Results from control groups (cell growth media and DMSO); and
  • B Results from groups treated with various concentrations of CC30 (10 ⁇ 40 ⁇ ).
  • FIG. 18 Graph of tumor volume over a 40 day time period showing the growth of CaSki cell transplanted tumors into BALB/c nude mice treated with CC30 or with solvent only (control).
  • FIG 19 Graph of tumor volume over a 26 day time period showing the growth of CaSki cell transplanted tumors into SCID mice treated with CC30 or with solvent only (control).
  • Figure 20 - Image shows on the top row the larger tumors extracted from BALB/c nude mice with transplanted HeLa cell tumors and treated with solvent only.
  • the bottom row displays small tumors extracted from BALB/c nude mice with transplanted HeLa cell tumors and treated with CC30.
  • One aspect of the disclosure relates to a method of treating cervical cancer and/or ovarian cancer in a subject comprising administering to the subject a therapeutically effectively amount of one or more transcription factor modulators disclosed herein or a pharmaceutical composition thereof.
  • the cervical cancer treated is metastatic cervical cancer. In certain embodiments, the cervical cancer treated is positive for HPV 16. In certain embodiments, the cervical cancer treated is positive for HPV 18. In certain embodiments, the cervical cancer treated is positive for HPV 16 and HPV 18. In certain embodiments, the cervical cancer treated is negative for HPV. In certain embodiments, the ovarian cancer treated is resistant to estrogen therapies. In certain embodiments, the ovarian cancer treated is resistant to anti-estrogen therapies. In certain embodiments, the anti-estrogen therapy is tamoxifen.
  • the one or more transcription factor modulators disclosed herein comprise a structure of CC54:
  • CC54 including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, further including mixtures thereof in all ratios.
  • CC54 refers to "Compound 1" as provided in International Patent Application No. PCT/CN2013/072247, filed March 6, 2013 and International Patent Application No. PCT/CN2013/072576, filed March 14, 2013, to which this application claims priority.
  • the one or more transcription factor modulators disclosed herein comprise a structure of Structure I:
  • Structure I including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, further including mixtures thereof in all ratios, wherein:
  • a and B rings are independently selected from the group consisting of phenyl, pyridyl and N-alkylated pyridyl rings;
  • R1-R5 are independently selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyi, wherein at least one or two of R1-R5 are halogen and/or haloalkyi;
  • Li is -(CH 2 ) n -, where n is 4, 5, 6, 7, or 8.
  • a ring is phenyl ring
  • B ring is pyridyl ring or N-alkylated pyridyl ring.
  • both A and B rings are phenyl rings.
  • a ring is pyridyl ring
  • B ring is phenyl ring or N-alkylated pyridyl ring.
  • both A and B rings are pyridyl rings.
  • a ring is N-alkylated pyridyl ring
  • B ring is phenyl ring or pyridyl ring.
  • both A and B rings are N-alkylated pyridyl rings.
  • R 4 and/or R 5 are/is haloalkyl (e.g. trifluoromethyl).
  • R 4 and/or R 5 are/is halogen (e.g. Br).
  • one of R 4 and R5 is haloalkyl (e.g. trifluoromethyl), and the other is halogen (e.g. Br).
  • R3 and/or R 4 are/is haloalkyl (e.g. trifluoromethyl).
  • R3 and/or R 4 are/is halogen (e.g. Br).
  • one of R 3 and R 4 is haloalkyl (e.g. trifluoromethyl), and the other is halogen (e.g. Br).
  • the one or more transcription modulators disclosed herein comprise a structure of Structure II:
  • Structure II including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, further including mixtures thereof in all ratios, wherein Ri X-i, X 2 , and U are defined the same as above.
  • R 4 and/or R 5 are/is halogen (e.g. Br).
  • R 4 and/or R 5 are/is haloalkyl trifluoromethyl).
  • R3 and/or R 4 are/is halogen (e.g. Br).
  • R3 and/or R 4 are/is haloalkyl trifluoromethyl).
  • L-i is -(CH 2 ) n -, where n is 4, 5, 6, 7, or 8.
  • the one or more transcription factor modulators disclosed herein comprise a structure selected from the group consisting of Structures IIIA-IIIC:
  • Structure NIC including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, further including mixtures thereof in all ratios, wherein:
  • a ring, Ri ⁇ Rs, X-i , X 2 , and U are defined the same as above;
  • R 7 is alkyl group having 1 -3 carbon atoms (e.g. methyl).
  • the N-alkylated pyridine ring of Structures IIIA-I IIC 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).
  • R 4 and/or R 5 are/is haloalkyl (e.g. trifluoromethyl).
  • R 4 and/or R 5 are/is halogen (e.g. Br).
  • one of R 4 and R5 is haloalkyl (e.g. trifluoromethyl), and the other is halogen (e.g. Br).
  • R3 and/or R 4 are/is haloalkyl (e.g. trifluoromethyl).
  • R3 and/or R 4 are/is halogen (e.g. Br).
  • one of R3 and R 4 is haloalkyl (e.g. trifluoromethyl), and the other is halogen (e.g. Br).
  • a ring is phenyl ring.
  • a ring is pyridyl ring.
  • a ring is N-alkylated pyridyl ring.
  • L-i is -(CH 2 ) n -, where n is 4, 5, 6, 7, or 8.
  • the one or more transcription factor modulators disclosed herein comprise a structure selected from the group consisting of Structures IVA-IVD:
  • Structure IVC Structure IVD, including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, further including mixtures thereof in all ratios, wherein:
  • R6 is alkyl group having 1 -3 carbon atoms (e.g. methyl).
  • 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).
  • suitable counterions e.g., without limitations, anions derived from pharmaceutically acceptable acids described herein, acetate, fluoroacetate or other carboxylate.
  • R 4 and/or R 5 are/is haloalkyl (e.g. trifluoromethyl).
  • R 4 and/or R 5 are/is halogen (e.g. Br).
  • one of R 4 and R5 is haloalkyl trifluoromethyl), and the other is halogen (e.g. Br).
  • one of R3 and R 4 is haloalkyl trifluoromethyl), and the other is halogen (e.g. Br).
  • R3 and/or R 4 are/is halogen (e.g. Br).
  • one of R3 and R 4 is haloalkyl trifluoromethyl), and the other is halogen (e.g. Br).
  • B ring is phenyl ring.
  • B ring is pyridyl ring.
  • B ring is N-alkylated pyridyl ring.
  • L-i is -(CH 2 ) n -, where n is 4, 5, 6, 7, or 8.
  • the one or more transcription factor modulators disclosed herein comprise a structure selected from the group consisting of Structures VII A ⁇ VI IE:
  • Structure VI IE including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, further including mixtures thereof in all ratios, wherein A ring, B ring, Ri ⁇ R 7 , X-i , X 2 , and U are defined the same as above.
  • 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).
  • suitable counterions e.g., without limitations, anions derived from pharmaceutically acceptable acids described herein, e.g. acetate, fluoroacetate or other carboxylate.
  • L-i is -(CH 2 ) n -, where n is 4, 5, 6, 7, or 8.
  • the one or more transcription modulators disclosed herein comprise a structure of Structure VIII:
  • Structure VII I including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, further including mixtures thereof in all ratios, wherein n, X-i, and X 2 are defined the same as above.
  • n 4, 5, 6, 7, or 8.
  • the one or more transcription modulators disclosed herein comprise a structure of CC30:
  • CC30 including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, and further including mixtures thereof in all ratios.
  • CC30 refers to "Compound 1" as provided in U.S. Provisional Application Serial No. 61 /773,789, filed March 6, 2013, to which this application claims priority.
  • the one or more transcription factor modulators disclosed herein comprise a structure of Formula I:
  • Formula I including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, and further including mixtures thereof in all ratios, wherein:
  • Ai and Bi rings are each independently selected from the group consisting of phenyl, pyridyl and N-alkylated pyridyl rings;
  • R-H-R-I5 are each independently selected from the group consisting of hydrogen, halogen and alkyl, wherein one or two of R11-R15 are halogens;
  • l_n is -(CH 2 ) n r, where n- ⁇ is 4, 5, 6, 7, or 8.
  • Ai ring is a phenyl ring
  • Bi ring is a pyridyl ring or N-alkylated pyridyl ring.
  • both Ai and Bi rings are phenyl rings.
  • Ai ring is a pyridyl ring
  • Bi ring is a phenyl ring or N-alkylated pyridyl ring.
  • both Ai and Bi rings are pyridyl rings.
  • Ai ring is an N-alkylated pyridyl ring
  • Bi ring is a phenyl ring or pyridyl ring.
  • both Ai and Bi rings are N-alkylated pyridyl rings.
  • 4 are/is halogen (e.g. Br).
  • Ri 4 and/or R-15 are/is halogen (e.g. Br).
  • the one or more transcription factor modulators disclosed herein comprise a structure of Formula II:
  • Formula II including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, and further including mixtures thereof in all ratios, wherein R-n-R-15, X-1 1 , X-I2, and l_n are defined the same as above.
  • 4 are/is halogen (e.g. Br).
  • Ri 4 and/or R15 are/is halogen (e.g. Br).
  • l_n is -(CH 2 ) n r, where n- ⁇ is 4, 5, 6, 7, or 8.
  • the one or more transcription factor modulators disclosed herein comprise a structure selected from the group consisting of Formulas IIIA-IIIC:
  • Formula N IC including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, and further including mixtures thereof in all ratios, wherein:
  • A-i ring, R11-R15, X11 , X12, and l_n are defined the same as above;
  • R-17 is an alkyl group having 1 -3 carbon atoms (e.g. methyl).
  • the N-alkylated pyridine ring of Formulas I MANIC 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).
  • suitable counterions e.g., without limitations, anions derived from pharmaceutically acceptable acids described herein, e.g. acetate, fluoroacetate or other carboxylate.
  • Ri 4 and/or R15 are/is halogen (e.g. Br).
  • one of Ri 4 and R-15 is halogen (e.g. Br), and the other is haloalkyl (e.g. trifluoromethyl).
  • Ri 3 and/or R 4 are/is halogen (e.g. Br).
  • one of Ri 3 and Ri 4 is halogen (e.g. Br), and the other is haloalkyl (e.g. trifluoromethyl).
  • A-i ring is a phenyl ring.
  • A-i ring is a pyridyl ring.
  • a ring is an N-alkylated pyridyl ring.
  • n is 4, 5, 6, 7, or 8.
  • the one or more transcription factor modulators disclosed herein comprise a structure selected from the group consisting of Formulas IVA-IVD:
  • Formula IVC Formula IVD including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, and further including mixtures thereof in all ratios, wherein:
  • R-I6 is an alkyl group having 1 -3 carbon atoms (e.g. methyl).
  • the N-alkylated pyridine ring of Formulas 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).
  • suitable counterions e.g., without limitations, anions derived from pharmaceutically acceptable acids described herein, acetate, fluoroacetate or other carboxylate.
  • Ri 4 and/or R15 are/is halogen (e.g. Br).
  • 4 are/is halogen (e.g. Br).
  • Bi ring is a phenyl ring.
  • Bi ring is a pyridyl ring.
  • Bi ring is an N-alkylated pyridyl ring.
  • l_n is -(CH 2 ) n r, where n- ⁇ is 4, 5, 6, 7, or 8.
  • the one or more transcription factor modulators disclosed herein comprise a structure selected from the group consisting of Formulas VA-VE:
  • Formula VE including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, and further including mixtures thereof in all ratios, wherein Ai ring, ⁇ - ⁇ ring, R-n-R 7 , X-n, X 2 , and are defined the same as above.
  • the N-alkylated pyridine ring of Formulas 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).
  • suitable counterions e.g., without limitations, anions derived from pharmaceutically acceptable acids described herein, e.g. acetate, fluoroacetate or other carboxylate.
  • l_n is -(CH 2 ) n r, where n- ⁇ is 4, 5, 6, 7, or 8.
  • the one or more transcription factor modulators disclosed herein comprise a structure of Formula VI: Formula VI including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, and further including mixtures thereof in all ratios, wherein n-i , Xii , and Xi 2 are defined the same as above.
  • ni is 4, 5, 6, 7, or 8.
  • alkyl refers to a straight or branched chain hydrocarbon having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.
  • 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 Ci-C6 alkyl linker as defined above. Such a ring may be optionally fused to one or more other aryl ring(s).
  • alkyl linker through which it may be attached, preferably a Ci-C6 alkyl linker as defined above.
  • alkyl linker such as a a Ci-C6 alkyl linker as defined above.
  • alkyl linker such as phenyl ring
  • aryl include, but are not limited to, phenyl, 2-naphthyl, 1 -naphthyl, biphenyl, imidazolyl as well as substituted derivatives thereof.
  • halogen refers to fluorine (F), chlorine (CI), bromine (Br) or iodine (I).
  • haloalkyl refers to an alkyl group wherein one or more hydrogen and/or carbon atoms are substituted with halogen atom.
  • 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.
  • solvate refers to a complex of variable stoichiometry formed by a solute (e.g., transcription factor modulators disclosed herein) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, aqueous solution (e.g. buffer), methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, aqueous solution (e.g. buffer), ethanol and acetic acid.
  • the solvent used is water or aqueous solution (e.g. buffer).
  • suitable solvates are the mono- or dihydrates or alcoholates of the compound according to the invention.
  • additive salt of the compound e.g. CC54 and/or CC30.
  • Suitable bases include organic and inorganic acids.
  • Suitable bases include organic and
  • inorganic acids include, but are not limited to: hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid.
  • 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,
  • suitable inorganic bases include, but are not limited to: ammonia, hydroxyethylamine and hydrazine.
  • 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
  • the transcription factor modulators 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, the transcription factor modulators disclosed herein include mixtures of
  • the transcription factor modulators disclosed herein also include the individual isomers of the compound represented by the structure of CC54 and/or CC30 above as well as any wholly or partially equilibrated mixtures thereof.
  • the transcription factor modulators disclosed herein also cover the individual isomers of the compound represented by the structure of CC54 and/or CC30 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 structure of CC54 and/or CC30 are included within the scope of the structure of CC54 and/or CC30 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.
  • 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.
  • 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.
  • a pharmaceutical composition comprises a
  • the composition comprising one or more transcription factor modulators disclosed herein (e.g. CC54 and/or CC30).
  • the transcription factor modulators e.g. CC54 and/or CC30.
  • composition further comprises a pharmaceutically acceptable carrier.
  • 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 transcription factor modulators disclosed herein or pharmaceutical compositions 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 one or more transcription factor modulators disclosed herein or the pharmaceutical composition thereof is administered alone or in combination with other drug(s), other therapy/therapies or other therapeutic method(s) or modality/modalities.
  • a typical dosage may range from about 0.1 mg/kg to about 100 mg/kg or more, depending on the factors mentioned above.
  • 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.
  • Remington The Science and Practice of Pharmacy, 21 st 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.
  • 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 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; (1 1 ) 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
  • compositions 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 transcription factor modulators disclosed herein (e.g. CC54 and/or CC30) in these pharmaceutical compositions 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.
  • the concentration of the one or more transcription factor modulators 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.
  • compositions containing the one or more transcription factor modulators disclosed herein 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.
  • the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution.
  • the pharmaceutically acceptable carrier is a solid and the
  • composition is in the form of a powder, tablet, pill, or capsules.
  • pharmaceutical carrier is a gel and the pharmaceutical composition 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.
  • the carrier is a finely divided solid that is in admixture with the finely divided active ingredient.
  • 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 (e.g. CC54 and/or CC30).
  • 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.
  • the pharmaceutical composition may also include suitable diluents, preservatives, solubilizers, emulsifiers, adjuvant and/or carriers.
  • the pharmaceutical composition 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.
  • 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.
  • sustained- or controlled-delivery formulations include 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 compositions.
  • 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.
  • kits for producing a single-dose administration unit may each contain both a first container having dried components and a second container having a formulation comprising a pharmaceutically acceptable carrier (e.g. an aqueous formulation). Also included within the scope of this invention are kits containing single and multi-chambered pre-filled syringes (e.g., liquid syringes and lyosyringes).
  • Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular transcription factor modulators 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 pharmaceutical composition may be effected continuously or intermittently. In any treatment regimen, the pharmaceutical composition may be administered to a subject either singly or in a cocktail containing two or more transcription factor modulators, 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, 41 st Ed., Publisher Edward R.
  • 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.
  • 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.
  • 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. Treatment may also mean a prophylactic or preventative treatment of a condition.
  • the one or more transcription factor modulators disclosed herein are administered in combination with a therapeutic agent or radiotherapy.
  • Another embodiment relates to the use of one or more transcription factor modulators disclosed herein, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of cervical cancer and/or ovarian cancer.
  • the one or more transcription factor modulators and the pharmaceutical compositions thereof are the same as disclosed above, and the treatment of cervical cancer and/or ovarian cancer is the same as described supra.
  • the cervical cancer treated is metastatic cervical cancer.
  • the cervical cancer treated is positive for HPV 16.
  • the cervical cancer treated is positive for HPV 18.
  • the cervical cancer treated is positive for HPV 16 and HPV 18.
  • the cervical cancer treated is negative for HPV.
  • the ovarian cancer treated is resistant to estrogen therapies.
  • the ovarian cancer treated is resistant to anti-estrogen therapies.
  • the anti-estrogen therapy is tamoxifen.
  • Example 1 CC54 inhibited proliferation of cervical cancer cells and induced apoptosis of human cervical and ovarian cancer cells.
  • the CellTiter-Glo cell Luminescent Cell Viability assay kit from Promega (Madison, Wl) was used to determine cell viability according to the manufacturer's protocol.
  • CC54 CC54 induced apoptosis of cervical and ovarian cancer cells by microscopy and flow cytometry.
  • HeLa HPV 18 positive
  • CaSki HPV 16 and 18 positive
  • C33A HPV negative human cervical cancer cells
  • SKOV3 growth-resistant to estrogens and anti-estrogens
  • Flow cytometry was used to detect the early and late apoptotic cells.
  • the apoptotic index (Al) was calculated and it represented the percentage of apoptotic cells in the total cell population detected by microscopy or flow cytometry.
  • CC54 significantly inhibited the growth of cervical cancer cells. CC54 significantly inhibited the growth of HeLa ( Figures 1A-1 C) and CaSki cervical cancer cells ( Figures 2A-2C) over different time points. In contrast, the human fibroblast and L929 mouse fibroblast cells serving as normal cell controls had a significantly lower sensitivity to CC54 than the CaSki and HeLa cervical cancer cell lines (Table 1 and Figure 3).
  • CC54 induced apoptosis in cervical and ovarian cancer cells.
  • CC54 induced apoptosis was detected by microscopy and flow cytometry.
  • Flow cytometry data show the distribution of CC54 treated HeLa ( Figure 4B), CaSki ( Figure 5B), C33A ( Figure 6B), and SKOV3 ( Figure 7B) cells in different stages of apoptosis.
  • HeLa, CaSki, C33A, and SKOV3 cells were treated with no solvent or DMSO only for the same time as controls, respectively ( Figures 4A, 5A, 6A, and 7A).
  • Tables 2-5 summarize the early, late, and total apoptotic indices determined from the microscopy and flow cytometry data for cervical cancer cells (HeLa, CaSki, and C33A) and ovarian cancer cells (SKOV3) treated with CC54.
  • apoptotic index (Al) calculated by flow cytometry indicated that the treatment of the HeLa (Table 2), CaSki (Table 3), C33A (Table 4), and SKOV3 (Table 5) cells with CC54 for 48 hours exhibited a significant increase in apoptosis as the dosage of the compounds increased.
  • CC54 induced apoptosis in the SKOV3 cells in a dose dependent manner suggests that those compounds also inhibited the growth of this ovarian cancer cell line (Table 5). Additionally, the data shows that CC54 inhibited the growth of ovarian cancer cells, such as SKOV3, that are growth-resistant to estrogen and anti-estrogens (Hua et. al., 1995).
  • Example 2 CC30 inhibited proliferation of cervical cancer cells and induced apoptosis of human cervical and ovarian cancer cells.
  • the CellTiter-Glo cell Luminescent Cell Viability assay kit from Promega (Madison, Wl) was used to determine cell viability according to the manufacturer's protocol.
  • CC30 Detection of CC30 induced apoptosis and growth inhibition for CaSki, SiHa, HeLa, and C4I cervical cancer cells.
  • Human cervical cancer cells, CaSki (HPV16 positive), SiHa (HPV16 positive), HeLa (HPV18 positive), and C4I (HPV18 positive) were seeded according to the method described above.
  • the cells were treated with CC30 having concentrations ranging from 5 ⁇ to 20 ⁇ . Cell viability and growth inhibition rates were determined as described above.
  • Caspase 3/7 a pivotal effector caspases in the apoptotic pathway
  • Apoptosis of the CaSki cells was detected by Hoechest 33258 fluorescence staining.
  • CaSki cells were treated with 20 ⁇ CC30 for 48 hours and stained with 30 ⁇ g/ml.
  • Hoechst 33258 fluorescence dye was added at 37°C to a final concentration of 30 ⁇ g/ml. After staining for 1 hour in the dark at 37°C.
  • Cells with bright, fragmented, condensed nuclei were identified as apoptotic cells using a fluorescence microscope.
  • DMSO was used for the control group.
  • the apoptotic rate was calculated by counting three to five random fields totaling at least 500 cells.
  • CC30 induced apoptosis of cervical and ovarian cancer cells by microscopy and flow cytometry.
  • HeLa, CaSki, and C33A human cervical cancer cells and SKOV3 human ovarian cancer cells were grown to the logarithmic phase, plated as described above, and treated with different concentrations of CC30 for 48 hours.
  • Annexin V/PI stained cells were observed by confocal laser scanning microscopy.
  • Flow cytometry was used to detect the early and late apoptotic cells.
  • the apoptosis index (Al) was calculated and it represented the percentage of apoptotic cells in the total cell population detected by microscopy or flow cytometry.
  • CC30 significantly inhibited the growth of cervical cancer cells. CC30 significantly inhibited the growth of HeLa ( Figures 8A-8C) and CaSki cervical cancer cells ( Figures 9A-9C) at different time points. In contrast, the human fibroblast and L929 mouse fibroblast cells serving as normal cell controls had a significantly lower sensitivity to CC30 than the CaSki and HeLa cervical cancer cell lines (Table 6 and Figure 10).
  • Figure 1 1 shows that the cell proliferations were inhibited for all four cervical cancer cell lines (CaSki, SiHa, HeLa, and C4I) with the treatment of CC30 at the concentrations ranging from 5 ⁇ to 20 ⁇ .
  • the increase in cell growth inhibition was proportional to the increased dose of treatment with CC30 ( Figure 1 1 ).
  • CC30 inhibited the cell growth of the cervical cancer cell lines in a dose dependent manner.
  • CC30 induced apoptosis in cervical and ovarian cancer cells.
  • CC30 treatment induced a dose dependent increase of apoptosis in the different cervical cancer cell lines (CaSki, SiHa, HeLa, and C4I) ( Figure 12).
  • the apoptosis in the different cell types was observed as an increase in Caspase 3/7 cellular levels ( Figure 12).
  • Caspase 3/7 activity increased significantly more in HPV16-positive CaSki and SiHa cell lines in comparison to the HPV18-positive HeLa and C4I cell lines ( Figure 12).
  • CC30 induced apoptosis was also detected by microscopy and flow cytometry.
  • Flow cytometry data showed the distribution of CC30 treated HeLa ( Figure 14B), CaSki ( Figure 15B), C33A ( Figure 16B), and SKOV3 ( Figure 17B) cells in different stages of apoptosis.
  • HeLa, CaSki, C33A, and SKOV3 cells were treated with cell growth media or DMSO only for the same time as controls, respectively ( Figures 14A, 15A, 16A, and 17A).
  • Tables 7-10 summarize the early, late, and total apoptotic indices determined from the microscopy and flow cytometry data for cervical cancer cells (HeLa, CaSki, and C33A) and ovarian cancer cells (SKOV3) treated with CC30.
  • apoptotic index (Al) calculated by flow cytometry indicated that the treatment of the HeLa (Table 7), CaSki (Table 8), C33A (Table 9), and SKOV3 (Table 10) cells with CC30 for 48 hours exhibited a significant increase in apoptosis as the dosage of the compounds increased. That CC30 induced apoptosis in the SKOV3 cells in a dose dependent manner suggests that those compounds also inhibited the growth of ovarian cancer cells (Table 10).
  • Example 3 CC30 significantly inhibited the growth of transplanted cervical cancer tumors in BALB/c nude mice and SCID mice.
  • mice Female BALB/c nu/nu nude mice that were 4-5 weeks old and had an average weight of 18.06 ⁇ 0.72 grams were used in the experiment. The mice were fed under specific pathogen free (SP) conditions. Food and water were available to the mice at will. Ten BALB/c nude mice were randomly divided into two groups as the CC30 treated group and the solvent control group with five mice in each group. A suspension of 5 x 10 6 cells per mouse CaSki cells (0.2 ml.) in logarithmic phase were innoculated subcutaneously into the right back of the BALB/c nude mice.
  • SP pathogen free
  • mice and the growth of the transplanted tumor were monitored. After 1 week when the transplanted tumor grew to 0.3-0.5 cm in diameter, the treated group received an intraperitoneal injection of CC30 (200 ⁇ _ volume; 50 mg/kg) once a day, 5 times a week, and for 5 weeks.
  • the control group received an intraperitoneal injection of the solvent (20% DMSO, 80% of 20% w/v (2-Hydroxypropyl)-3-cyclodextrin made in PBS).
  • the BALB/c nude mice were euthanized - if weight loss was more than 20% or the tumor diameter reached 1 .5 cm during the experiment.
  • the BALB/c nude mice were euthanized on the next day after the final injection.
  • Tumor and vital organs, such as liver, kidney and spleen, from each mouse were carefully dissected out, weighed, and divided into two parts.
  • One piece was fixed in 10% buffered formalin and used for histopathology or immunohistochemistry.
  • the second piece was snap frozen in liquid nitrogen and stored at -80°C. Paraffin sections were routinely stained with hematoxylin - eosin (HE). The pathological changes of the transplanted tumor, liver and kidney were observed under an optical microscope.
  • HE hematoxylin - eosin
  • SCID mice Tumor transplantation and treatment of SCID mice.
  • CaSki cervical cancer cells were transplanted into CB1 severe combined immunodeficiency (SCID) female mice and treated with CC30 using the same experimental method and treatment protocol as described above for the BALB/c nude mice. All experimental procedures were the same as described above except that the SCID mice were euthanized 26 days rather than 40 days after treatment.
  • the transplanted tumors in the control group of SCID mice grew to a diameter greater than 1 .5 cm by day 26 and had to be sacrificed at the earlier time point.
  • CC30 inhibited the growth of transplanted tumors in BABUc mice.
  • One week after seeding the BALB/c nude mice with CaSki cells all of the transplanted tumors grew to a diameter of approximately 0.3-0.5 cm. The rate of successful transplantation was 100%.
  • the tumor volume of the control group was 639.37 ⁇ 329.28 mm 3
  • the tumor volume of the CC30 treated group was 88.14 ⁇ 96.57 mm 3 (Table 1 1 ).
  • the tumor inhibition rate of the treated group was 85% compared to the control group.
  • the tumor weight was significantly less than that of the control group, and the difference was statistically significant ( Figure 18 and Table 1 1 ).
  • Table 11 Body weight and tumor size of BABL/c nude mice with transplanted cervical cancer tumors
  • CC30 significantly inhibited the growth of CaSki tumors in mice. No apparent changes in body weight, behavior, activity or posture, areas of redness and swelling, and food and water withdrawal, were observed in the CC30 treated group. The morphology and organizational structure of liver and kidney in the CC30 appeared normal by HE staining in the CC30 treated group. No inflammatory cell infiltration on liver cells, no denaturation, hemorrhage and necrosis, and no central venous expansion were observed in the CC30 treated mice.
  • CC30 inhibited the growth of transplanted tumors in SCID mice.
  • the tumor volume of the control group was 799.63 ⁇ 167.56 mm 3
  • the tumor volume of the CC30 treated group was 415.37 ⁇ 146.03 mm 3 (Table 12).
  • the tumor inhibition rate of the CC30 treated group was approximately 50%.
  • the tumor weight of the CC30 treated group was significantly less than that of the control group, and the difference was statistically significant (Figure 19 and Table 12).
  • Example 4 CC30 significantly inhibited the growth of HeLa transplanted tumors in BALB/c nude mice.
  • BALB/c nu/nu nude mice 4-5 weeks old, female, were fed under SPF (specific pathogen free) conditions. Food and water were available to mice at will. Twenty-five BALB/c nude mice were randomly divided into 3 subgroups with 5 mice per group: intraperitoneal injection (IP) solvent control group, IP CC30 treatment group, and oral cisplatin treatment group.
  • IP intraperitoneal injection
  • HeLa cells (200 ⁇ ) in logarithmic phase were seeded subcutaneously on the right back of the nude mice (about 3 * 0 6 cells for each mouse). The general conditions of the mice and the growth of the transplanted tumor were observed.
  • the IP CC30 treatment group was intraperitoneally injected with 50mg/KG (injection volume 200uL) of CC30, once a day, 5 times a week, while the IP control group was injected intraperitoneally with 200 ⁇ of solvent (20% DMSO, 20% w/v (2-Hydroxypropyl)-3- cyclodextrin made by 80% PBS), following the same administration schedule.
  • the cisplatin treatment group was gavaged with 5 mg/kg of cisplatin once per week and served as a positive control to ensure the validity of the model.
  • mice The body weights of mice were measured at least twice a week and the total dose was adjusted according to body weight.
  • T/C % (Tumor weight of treatment group / Tumor weight of control group with same mode of administration) X 100.
  • CC30 significantly inhibited growth of the transplanted tumor when injected intraperitoneally (Table 13 and Figure 20).
  • Figure 20 shows the significantly smaller tumors that were extracted from the mice in the IP CC30 treatment group as compared to those extracted from the IP control group ( Figure 20).
  • Table 13 CC30 inhibited the growth of tumors in BALB/c nude mice transplanted with HeLa cervical cancer cells
  • SKOV3 ovarian carcinoma cells have functional estrogen receptor but are growth-resistant to estrogen and antiestrogens. (1995) J. Steroid Biochem. Mol. Biol. 55(3-4): 279-289.

Abstract

One aspect of the invention relates to new transcription factor modulators and pharmaceutical compositions thereof. Another aspect of the invention relates to a method of treating cervical cancer and/or ovarian cancer by administering a therapeutically effective amount of one or more transcription factor modulators disclosed herein, or a pharmaceutical composition thereof.

Description

TREATMENT OF CERVICAL CANCER AND/OR OVARIAN CANCER USING A TRANSCRIPTION FACTOR MODULATOR
PRIORITY CLAIM
[0001] This application claims priority to International Patent Application No. PCT/CN2013/072247, filed March 6, 2013; International Patent Application No. PCT/CN2013/072576, filed March 14, 2013; and U.S. Provisional Application Serial No. 61 /773,789, filed March 6, 2013, which are incorporated herein by reference in their entirety, as if fully set forth herein.
BACKGROUND
[0002] Cervical cancer is the third most common and one of the most deadly cancers affecting women, with an estimated 530,000 new cases and 275,000 deaths each year (Ferlay et. al., 2010). As the world's most populous country, with 70% of its population living in rural areas, China accounts for 14% of the world's annual incidence of cervical cancer (75,500 new cases) and 12% of the world's annual mortality from cervical cancer (34,000 deaths) (Ferlay et. al., 2010). Negative outcomes associated with cervical cancer are largely due to limited accessibility to efficient identification methods at early stages in developing countries and the high tendency of metastasis.
[0003] There is no specific cure for cervical cancer. Current clinical approaches involve using a chemotherapy drug combination, such as platinum- based cytotoxic drugs, and radiation therapy (Candelaria et al., 2006). For patients with metastatic and recurrent cervical cancer, cure rates using these treatment options are low, with an effective rate of only 30-50% (Scatchard et al., 2012). Furthermore, these chemotherapeutic drugs are generally very toxic and can have severe adverse side effects on general health and life quality of patients. Chemotherapy drugs (including cisplatin and carboplatin) generally function 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. Mainstream cytotoxic chemotherapy drugs act in a non-specific manner and kill both tumor and normal cells. Moreover, by interfering with DNA synthesis, chemotherapy drugs may also induce new DNA mutations that may result in the occurrence of new cancer incidences.
[0004] 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 cervical cancer and/or ovarian cancer with therapeutic benefits and limited side effects.
SUMMARY
[0005] One aspect of the invention relates to a method of treating cervical cancer and/or ovarian cancer by administering one or more transcription factor modulators disclosed herein, or a pharmaceutical composition thereof.
[0006] Another aspect of the invention relates to the use of one or more transcription factor modulators disclosed herein, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of cervical cancer and/or ovarian cancer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] Figure 1 - Dose dependent growth inhibition of HeLa cells by CC54. (A) Effects of CC54 after treatment of 24 hours; (B) Effects of CC54 after treatment of 48 hours; and (C) Effects of CC54 after treatment of 72 hours.
[0008] Figure 2 - Dose dependent growth inhibition of CaSki cells by CC54. (A) Effects of CC54 after treatment of 24 hours; (B) Effects of CC54 after treatment of 48 hours; and (C) Effects of CC54 after treatment of 72 hours.
[0009] Figure 3 - Dose dependent growth inhibition of L292 cells by CC54 after treatment of 48 hours.
[0010] Figure 4 - Flow cytometry data showing CC54 induced early (quadrant B1 ) and late (quadrant B4) stage apoptosis in HeLa cervical cancer cells. (A). Results from control groups (no solvent and DMSO); and (B) Results from groups treated with various concentrations of CC54 (10 μΜ~40 μΜ).
[001 1] Figure 5 - Flow cytometry data showing CC54 induced early (quadrant B1 ) and late (quadrant B4) stage apoptosis in CaSki cervical cancer cells. (A) Results from control groups (no solvent and DMSO); and (B) Results from groups treated with various concentrations of CC54 (10 μΜ~40 μΜ).
[0012] Figure 6 - Flow cytometry data showing CC54 induced early (quadrant B1 ) and late (quadrant B4) stage apoptosis in C33A cervical cancer cells. (A) Results from control groups (no solvent and DMSO); and (B) Results from groups treated with various concentrations of CC54 (10 μΜ~40 μΜ).
[0013] Figure 7 - Flow cytometry data showing CC54 induced early (quadrant B1 ) and late (quadrant B4) stage apoptosis in SKOV3 ovarian cancer cells. (A) Results from control groups (no solvent and DMSO); and (B) Results from groups treated with various concentrations of CC54 (10 μΜ~40 μΜ).
[0014] Figure 8 - Dose dependent growth inhibition of HeLa cells by CC30. (A) Effects of CC30 after treatment of 24 hours; (B) Effects of CC30 after treatment of 48 hours; and (C) Effects of CC30 after treatment of 72 hours.
[0015] Figure 9 - Dose dependent growth inhibition of CaSki cells by CC30. (A) Effects of CC30 after treatment of 24 hours; (B) Effects of CC30 after treatment of 48 hours; and (C) Effects of CC30 after treatment of 72 hours.
[0016] Figure 10 - Dose dependent growth inhibition of L292 cells by CC30 after treatment of 48 hours.
[0017] Figure 1 1 - Dose dependent growth inhibition of CaSki, SiHa, HeLa, and C4I cells by CC30.
[0018] Figure 12 - Dose dependent induction of apoptosis in CaSki, SiHa, HeLa, and C4I cells by CC30 observed as an increase in Caspase 3/7 activity.
[0019] Figure 13 - Hoechest 33258 fluorescence staining of the CaSki cells. (A) Apoptotic CaSki cells treated with CC30; and (B) Normal and healthy CaSki cells treated with DMSO.
[0001] Figure 14 - Flow cytometry data showing CC30 induced early (quadrant B1 ) and late (quadrant B4) stage apoptosis in HeLa cervical cancer cells. (A) Results from control groups (cell growth media and DMSO); and (B) Results from groups treated with various concentrations of CC30 (10 μΜ~40 μΜ).
[0002] Figure 15 - Flow cytometry data showing CC30 induced early (quadrant B1 ) and late (quadrant B4) stage apoptosis in CaSki cervical cancer cells. (A) Results from control groups (cell growth media and DMSO); and (B) Results from groups treated with various concentrations of CC30 (10 μΜ~40 μΜ).
[0003] Figure 16 - Flow cytometry data showing CC30 induced (quadrant B1 ) and late (quadrant B4) stage apoptosis in C33A cervical cancer cells. (A) Results from control groups (cell growth media and DMSO); and (B) Results from groups treated with various concentrations of CC30 (10 μΜ~40 μΜ).
[0004] Figure 17 - Flow cytometry data showing CC30 induced (quadrant B1 ) and late (quadrant B4) stage apoptosis in SKOV3 cervical cancer cells. (A) Results from control groups (cell growth media and DMSO); and (B) Results from groups treated with various concentrations of CC30 (10 μΜ~40 μΜ).
[0005] Figure 18 - Graph of tumor volume over a 40 day time period showing the growth of CaSki cell transplanted tumors into BALB/c nude mice treated with CC30 or with solvent only (control).
[0006] Figure 19 - Graph of tumor volume over a 26 day time period showing the growth of CaSki cell transplanted tumors into SCID mice treated with CC30 or with solvent only (control).
[0007] Figure 20 - Image shows on the top row the larger tumors extracted from BALB/c nude mice with transplanted HeLa cell tumors and treated with solvent only. The bottom row displays small tumors extracted from BALB/c nude mice with transplanted HeLa cell tumors and treated with CC30.
DETAILED DESCRIPTION
[0008] One aspect of the disclosure relates to a method of treating cervical cancer and/or ovarian cancer in a subject comprising administering to the subject a therapeutically effectively amount of one or more transcription factor modulators disclosed herein or a pharmaceutical composition thereof.
[0009] In certain embodiments the cervical cancer treated is metastatic cervical cancer. In certain embodiments, the cervical cancer treated is positive for HPV 16. In certain embodiments, the cervical cancer treated is positive for HPV 18. In certain embodiments, the cervical cancer treated is positive for HPV 16 and HPV 18. In certain embodiments, the cervical cancer treated is negative for HPV. In certain embodiments, the ovarian cancer treated is resistant to estrogen therapies. In certain embodiments, the ovarian cancer treated is resistant to anti-estrogen therapies. In certain embodiments, the anti-estrogen therapy is tamoxifen.
[0010] /. Transcription factor modulators
[001 1] In one embodiment, the one or more transcription factor modulators disclosed herein comprise a structure of CC54:
Figure imgf000008_0001
CC54, including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, further including mixtures thereof in all ratios. As used herein, "CC54" refers to "Compound 1 " as provided in International Patent Application No. PCT/CN2013/072247, filed March 6, 2013 and International Patent Application No. PCT/CN2013/072576, filed March 14, 2013, to which this application claims priority.
[0012] In another embodiment, the one or more transcription factor modulators disclosed herein comprise a structure of Structure I:
Figure imgf000009_0001
Structure I, including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, further including mixtures thereof in all ratios, wherein:
A and B rings are independently selected from the group consisting of phenyl, pyridyl and N-alkylated pyridyl rings;
R1-R5 are independently selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyi, wherein at least one or two of R1-R5 are halogen and/or haloalkyi;
Xi and X2 are independently selected from -NHC(=0)- or -C(=0)-NH-; and
Li 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 -0-, -S-, -C(=0)-, -S(=0)-, -S(=0)2-, -NH-C(=0)-, -C(=0)-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).
[0013] In certain embodiments, Li is -(CH2)n-, where n is 4, 5, 6, 7, or 8. [0014] In certain embodiments, -X L X2-\s -NHC(=0)-L1-C(=0)NH-.
[0015] In certain embodiments, -X l X2-\s -C(=0)-NH-L1-C(=0)NH-.
[0016] In certain embodiments, A ring is phenyl ring, and B ring is pyridyl ring or N-alkylated pyridyl ring.
[0017] In certain embodiments, both A and B rings are phenyl rings.
[0018] In certain embodiments, A ring is pyridyl ring, and B ring is phenyl ring or N-alkylated pyridyl ring.
[0019] In certain embodiments, both A and B rings are pyridyl rings.
[0020] In certain embodiments, A ring is N-alkylated pyridyl ring, and B ring is phenyl ring or pyridyl ring.
[0021] In certain embodiments, both A and B rings are N-alkylated pyridyl rings.
[0022] In certain embodiments, R4 and/or R5 are/is haloalkyl (e.g. trifluoromethyl).
[0023] In certain embodiments, R4 and/or R5 are/is halogen (e.g. Br).
[0024] In certain embodiments, one of R4 and R5 is haloalkyl (e.g. trifluoromethyl), and the other is halogen (e.g. Br).
[0025] In certain embodiments, R3 and/or R4 are/is haloalkyl (e.g. trifluoromethyl).
[0026] In certain embodiments, R3 and/or R4 are/is halogen (e.g. Br).
[0027] In certain embodiments, one of R3 and R4 is haloalkyl (e.g. trifluoromethyl), and the other is halogen (e.g. Br). [0028] In another embodiment, the one or more transcription modulators disclosed herein comprise a structure of Structure II:
Figure imgf000011_0001
Structure II, including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, further including mixtures thereof in all ratios, wherein Ri X-i, X2, and U are defined the same as above.
[0029] In certain embodiments, R4 and/or R5 are/is halogen (e.g. Br).
[0030] In certain embodiments, R4 and/or R5 are/is haloalkyl trifluoromethyl).
[0031] In certain embodiments, R3 and/or R4 are/is halogen (e.g. Br).
[0032] In certain embodiments, R3 and/or R4 are/is haloalkyl trifluoromethyl).
[0033] In certain embodiments, L-i is -(CH2)n-, where n is 4, 5, 6, 7, or 8. [0034] In certain embodiments, -X l X2-\s -NHC(=0)-L1-C(=0)NH-. [0035] In certain embodiments, -X l X2-\s -C(=0)-NH-L1-C(=0)NH-. [0036] In another embodiment, the one or more transcription factor modulators disclosed herein comprise a structure selected from the group consisting of Structures IIIA-IIIC:
Figure imgf000012_0001
Figure imgf000012_0002
Structure NIC, including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, further including mixtures thereof in all ratios, wherein:
A ring, Ri~Rs, X-i , X2, and U are defined the same as above; and
R7 is alkyl group having 1 -3 carbon atoms (e.g. methyl). [0037] In certain embodiments, the N-alkylated pyridine ring of Structures IIIA-I IIC 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).
[0038] In certain embodiments, R4 and/or R5 are/is haloalkyl (e.g. trifluoromethyl).
[0039] In certain embodiments, R4 and/or R5 are/is halogen (e.g. Br).
[0040] In certain embodiments, one of R4 and R5 is haloalkyl (e.g. trifluoromethyl), and the other is halogen (e.g. Br).
[0041] In certain embodiments, R3 and/or R4 are/is haloalkyl (e.g. trifluoromethyl).
[0042] In certain embodiments, R3 and/or R4 are/is halogen (e.g. Br).
[0043] In certain embodiments, one of R3 and R4 is haloalkyl (e.g. trifluoromethyl), and the other is halogen (e.g. Br).
[0044] In certain embodiments, A ring is phenyl ring.
[0045] In certain embodiments, A ring is pyridyl ring.
[0046] In certain embodiments, A ring is N-alkylated pyridyl ring.
[0047] In certain embodiments, L-i is -(CH2)n-, where n is 4, 5, 6, 7, or 8.
[0048] In certain embodiments, -X l X2-\s -NHC(=0)-L1-C(=0)NH-.
[0049] In certain embodiments, -X l X2-\s -C(=0)-NH-L1-C(=0)NH-.
[0050] In another embodiment, the one or more transcription factor modulators disclosed herein comprise a structure selected from the group consisting of Structures IVA-IVD:
Figure imgf000014_0001
Structure IVA, Structure IVB,
Figure imgf000014_0002
Structure IVC, Structure IVD, including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, further including mixtures thereof in all ratios, wherein:
B ring, R-i-Rs, X-i , X2, and L-i are defined the same as above; and
R6 is alkyl group having 1 -3 carbon atoms (e.g. methyl).
[0051] 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).
[0052] In certain embodiments, R4 and/or R5 are/is haloalkyl (e.g. trifluoromethyl). [0053] In certain embodiments, R4 and/or R5 are/is halogen (e.g. Br).
[0054] In certain embodiments, one of R4 and R5 is haloalkyl trifluoromethyl), and the other is halogen (e.g. Br).
[0055] In certain embodiments, one of R3 and R4 is haloalkyl trifluoromethyl), and the other is halogen (e.g. Br).
[0056] In certain embodiments, R3 and/or R4 are/is halogen (e.g. Br).
[0057] In certain embodiments, one of R3 and R4 is haloalkyl trifluoromethyl), and the other is halogen (e.g. Br).
[0058] In certain embodiments, B ring is phenyl ring.
[0059] In certain embodiments, B ring is pyridyl ring.
[0060] In certain embodiments, B ring is N-alkylated pyridyl ring.
[0061] In certain embodiments, L-i is -(CH2)n-, where n is 4, 5, 6, 7, or 8.
[0062] In certain embodiments, -X l X2-\s -NHC(=0)-L1-C(=0)NH-.
[0063] In certain embodiments, -X l X2-\s -C(=0)-NH-L1-C(=0)NH-.
[0064] In another embodiment, the one or more transcription factor modulators disclosed herein comprise a structure selected from the group consisting of Structures VII A~VI IE:
Figure imgf000015_0001
Structure VI IA, Structure VI IB,
Figure imgf000016_0001
Structure VI IC, Structure VI ID,
Figure imgf000016_0002
Structure VI IE, including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, further including mixtures thereof in all ratios, wherein A ring, B ring, Ri~R7, X-i , X2, and U are defined the same as above.
[0065] 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).
[0066] In certain embodiments, L-i is -(CH2)n-, where n is 4, 5, 6, 7, or 8.
[0067] In certain embodiments, -X L X2-is -NHC(=0)-L1-C(=0)NH-
[0068] In certain embodiments, -X L X2-is -C(=0)-NH-L1-C(=0)NH-. [0069] In another embodiment, the one or more transcription modulators disclosed herein comprise a structure of Structure VIII:
Figure imgf000017_0001
Structure VII I, including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, further including mixtures thereof in all ratios, wherein n, X-i, and X2 are defined the same as above.
[0070] In certain embodiments, n is 4, 5, 6, 7, or 8.
[0071] In certain embodiments, -Xi-(CH2)n-X2-is -NHC(=0)-(CH2)n-C(=0)NH-.
[0072] In certain embodiments, -Xi-(CH2)n-X2-is -C(=0)-NH- (CH2)n- C(=0)NH-.
[0073] In another embodiment, the one or more transcription modulators disclosed herein comprise a structure of CC30:
Figure imgf000017_0002
CC30, including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, and further including mixtures thereof in all ratios. As used herein, "CC30" refers to "Compound 1 " as provided in U.S. Provisional Application Serial No. 61 /773,789, filed March 6, 2013, to which this application claims priority.
[0074] In another embodiment, the one or more transcription factor modulators disclosed herein comprise a structure of Formula I:
Figure imgf000018_0001
Formula I, including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, and further including mixtures thereof in all ratios, wherein:
Ai and Bi rings are each independently selected from the group consisting of phenyl, pyridyl and N-alkylated pyridyl rings;
R-H-R-I5 are each independently selected from the group consisting of hydrogen, halogen and alkyl, wherein one or two of R11-R15 are halogens;
X11 and X-12 are each independently selected from -NHC(=0)- or -C(=0)-NH-; and
L-i-i is -(CH2)nr, where n-ι is 4, 5, 6, 7, or 8, optionally wherein one or more - CH2- moieties are replaced with one or more substituents selected from the group consisting of -0-, -S-, -C(=0)-, -S(=0)-, -S(=0)2-, -NH-C(=0)-, -C(=0)-NH-, -NR18- (wherein R-is is hydrogen, alkyl or aryl), -C=C-, carbon-carbon triple bond, phenylene (e.g. 1 , 4-phenylene) and cyclohexylene (e.g. 1 , 4-cyclohexylene).
[0075] In certain embodiments, l_n is -(CH2)nr, where n-ι is 4, 5, 6, 7, or 8.
[0076] In certain embodiments, -Xn-Li X12-is -NHC(=0)-Ln-C(=0)NH-.
[0077] In certain embodiments, -Xn-Li X12-is -C(=0)-NH-Ln-C(=0)NH-.
[0078] In certain embodiments, Ai ring is a phenyl ring, and Bi ring is a pyridyl ring or N-alkylated pyridyl ring.
[0079] In certain embodiments, both Ai and Bi rings are phenyl rings.
[0080] In certain embodiments, Ai ring is a pyridyl ring, and Bi ring is a phenyl ring or N-alkylated pyridyl ring.
[0081] In certain embodiments, both Ai and Bi rings are pyridyl rings.
[0082] In certain embodiments, Ai ring is an N-alkylated pyridyl ring, and Bi ring is a phenyl ring or pyridyl ring.
[0083] In certain embodiments, both Ai and Bi rings are N-alkylated pyridyl rings.
[0084] In certain embodiments, R13 and/or R-|4 are/is halogen (e.g. Br).
[0085] In certain embodiments, Ri4 and/or R-15 are/is halogen (e.g. Br).
[0086] In another embodiment, the one or more transcription factor modulators disclosed herein comprise a structure of Formula II:
Figure imgf000020_0001
Formula II including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, and further including mixtures thereof in all ratios, wherein R-n-R-15, X-1 1 , X-I2, and l_n are defined the same as above.
[0087] In certain embodiments, R13 and/or R-|4 are/is halogen (e.g. Br).
[0088] In certain embodiments, Ri4 and/or R15 are/is halogen (e.g. Br).
[0089] In certain embodiments, l_n is -(CH2)nr, where n-ι is 4, 5, 6, 7, or 8.
[0090] In certain embodiments, -Xn-Ln-X^-is -NHC(=0)-Ln-C(=0)NH-.
[0091] In certain embodiments, -Xn-Ln-X^-is -C(=0)-NH-Ln-C(=0)NH-.
[0092] In another embodiment, the one or more transcription factor modulators disclosed herein comprise a structure selected from the group consisting of Formulas IIIA-IIIC:
Figure imgf000021_0001
Formula N IC, including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, and further including mixtures thereof in all ratios, wherein:
A-i ring, R11-R15, X11 , X12, and l_n are defined the same as above; and
R-17 is an alkyl group having 1 -3 carbon atoms (e.g. methyl).
[0093] In certain embodiments, the N-alkylated pyridine ring of Formulas I MANIC 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).
[0094] In certain embodiments, Ri4 and/or R15 are/is halogen (e.g. Br). [0095] In certain embodiments, one of Ri4 and R-15 is halogen (e.g. Br), and the other is haloalkyl (e.g. trifluoromethyl).
[0096] In certain embodiments, Ri3 and/or R 4 are/is halogen (e.g. Br).
[0097] In certain embodiments, one of Ri3 and Ri4 is halogen (e.g. Br), and the other is haloalkyl (e.g. trifluoromethyl).
[0098] In certain embodiments, A-i ring is a phenyl ring.
[0099] In certain embodiments, A-i ring is a pyridyl ring.
[00100] In certain embodiments, A ring is an N-alkylated pyridyl ring.
[00101] In certain embodiments, is -(CH2)nr, where n is 4, 5, 6, 7, or 8.
[00102] In certain embodiments, -Xn-Ln-Xi2-is -NHC(=0)-Ln-C(=0)NH-.
[00103] In certain embodiments, -Xi Li Xi2-is -C(=0)-NH-Ln-C(=0)NH-.
[00104] In another embodiment, the one or more transcription factor modulators disclosed herein comprise a structure selected from the group consisting of Formulas IVA-IVD:
Figure imgf000022_0001
Formula IVA Formula IVB
Figure imgf000023_0001
Formula IVC Formula IVD including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, and further including mixtures thereof in all ratios, wherein:
B-i ring, R11-R15, X11 , X12, and l_n are defined the same as above; and
R-I6 is an alkyl group having 1 -3 carbon atoms (e.g. methyl).
[00105] In certain embodiments, the N-alkylated pyridine ring of Formulas 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).
[00106] In certain embodiments, Ri4 and/or R15 are/is halogen (e.g. Br).
[00107] In certain embodiments, R13 and/or R-|4 are/is halogen (e.g. Br).
[00108] In certain embodiments, Bi ring is a phenyl ring.
[00109] In certain embodiments, Bi ring is a pyridyl ring.
[001 10] In certain embodiments, Bi ring is an N-alkylated pyridyl ring.
[001 11] In certain embodiments, l_n is -(CH2)nr, where n-ι is 4, 5, 6, 7, or 8.
[001 12] In certain embodiments, -Xn-Ln-Xi2-is -NHC(=0)-Ln-C(=0)NH-. [00113] In certain embodiments, -Xn-Ln-X^-is -C(=0)-NH-Ln-C(=0)NH-
[00114] In another embodiment, the one or more transcription factor modulators disclosed herein comprise a structure selected from the group consisting of Formulas VA-VE:
Figure imgf000024_0001
Formula VA Formula VB
Figure imgf000024_0002
Formula VE, including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, and further including mixtures thereof in all ratios, wherein Ai ring, Β-ι ring, R-n-R 7, X-n, X 2, and are defined the same as above.
[001 15] In certain embodiments, the N-alkylated pyridine ring of Formulas 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).
[001 16] In certain embodiments, l_n is -(CH2)nr, where n-ι is 4, 5, 6, 7, or 8.
[001 17] In certain embodiments, -Xn-Li X12-is -NHC(=0)-Ln-C(=0)NH-.
[001 18] In certain embodiments, -Xn-Li X12-is -C(=0)-NH-Ln-C(=0)NH-.
[001 19] In another embodiment, the one or more transcription factor modulators disclosed herein comprise a structure of Formula VI:
Figure imgf000025_0001
Formula VI including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, and further including mixtures thereof in all ratios, wherein n-i , Xii , and Xi2 are defined the same as above.
[00120] In certain embodiments, ni is 4, 5, 6, 7, or 8.
[00121] In certain embodiments, -Xn-(CH2)ni-Xi2-is -NHC(=0)-(CH2)ni- C(=0)NH-. [00122] In certain embodiments, -Xn-(CH2)ni-Xi2-is -C(=0)-NH-(CH2)ni- C(=0)NH-.
[00123] As used herein, the term "comprise," or "comprising" is an open-ended transitional phrase meaning that all the following elements are included, but may also include additional, unnamed elements.
[00124] 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, 1 1 , 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).
[00125] 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 Ci-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.
[00126] As used herein, the term "halogen" or "halo" refers to fluorine (F), chlorine (CI), bromine (Br) or iodine (I).
[00127] 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.
[00128] 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.
[00129] As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (e.g., transcription factor modulators 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.
[00130] 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. CC54 and/or CC30). 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.
[00131] The transcription factor modulators 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, the transcription factor modulators disclosed herein include mixtures of
stereoisomers or mixtures of enantiomers, as well as purified stereoisomers, purified enantiomers, stereoisomerically enriched mixtures, or enantiomerically enriched mixtures. The transcription factor modulators disclosed herein also include the individual isomers of the compound represented by the structure of CC54 and/or CC30 above as well as any wholly or partially equilibrated mixtures thereof. The transcription factor modulators disclosed herein also cover the individual isomers of the compound represented by the structure of CC54 and/or CC30 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 structure of CC54 and/or CC30 are included within the scope of the structure of CC54 and/or CC30 and preferably the structures corresponding thereto.
[00132] 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.
[00133] 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.
[00134] //. Pharmaceutical compositions
[00135] As used herein, a pharmaceutical composition comprises a
therapeutically effective amount of one or more transcription factor modulators disclosed herein (e.g. CC54 and/or CC30). In certain embodiments, the
pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
[00136] 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.
[00137] This amount will vary depending upon a variety of factors, including but not limited to the characteristics of the transcription factor modulators disclosed herein or pharmaceutical compositions 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 one or more transcription factor modulators disclosed herein or the pharmaceutical composition 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 transcription factor modulators disclosed herein (e.g. CC54 and/or CC30) or the pharmaceutical composition 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, 21 st 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.
[00138] As used herein, the term "about" refers to ±10%, ±5%, or ±1 %, of the value following "about."
[00139] 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.
[00140] 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; (1 1 ) 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 nontoxic compatible substances employed in pharmaceutical formulations.
[00141] The pharmaceutical compositions 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.
[00142] The concentration of the one or more transcription factor modulators disclosed herein (e.g. CC54 and/or CC30) in these pharmaceutical compositions 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 one or more transcription factor modulators 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.
[00143] 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.
[00144] One skilled in the art will recognize that a pharmaceutical composition containing the one or more transcription factor modulators disclosed herein (e.g. CC54 and/or CC30) 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.
[00145] In one embodiment, the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In another embodiment, the pharmaceutically acceptable carrier is a solid and the
pharmaceutical composition is in the form of a powder, tablet, pill, or capsules. In another embodiment, the pharmaceutical carrier is a gel and the pharmaceutical composition is in the form of a suppository or cream.
[00146] 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 (e.g. CC54 and/or CC30). 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.
[00147] Besides containing an effective amount of the one or more transcription factor modulators described herein the pharmaceutical composition may also include suitable diluents, preservatives, solubilizers, emulsifiers, adjuvant and/or carriers.
[00148] The pharmaceutical composition 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.
[00149] Additional pharmaceutical compositions 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 compositions. 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.
[00150] In one embodiment, the pharmaceutical composition administered is made into kits for producing a single-dose administration unit. The kits may each contain both a first container having dried components and a second container having a formulation comprising a pharmaceutically acceptable carrier (e.g. an aqueous formulation). Also included within the scope of this invention are kits containing single and multi-chambered pre-filled syringes (e.g., liquid syringes and lyosyringes).
[00151 ] ///. Methods of treatment
[00152] Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular transcription factor modulators 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 pharmaceutical composition may be effected continuously or intermittently. In any treatment regimen, the pharmaceutical composition may be administered to a subject either singly or in a cocktail containing two or more transcription factor modulators, 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, 41 st 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.
[00153] "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. Treatment may also mean a prophylactic or preventative treatment of a condition.
[00154] In certain embodiments, the one or more transcription factor modulators disclosed herein (e.g. CC54 and/or CC30) are administered in combination with a therapeutic agent or radiotherapy.
[00155] Another embodiment relates to the use of one or more transcription factor modulators disclosed herein, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of cervical cancer and/or ovarian cancer. For this aspect, the one or more transcription factor modulators and the pharmaceutical compositions thereof are the same as disclosed above, and the treatment of cervical cancer and/or ovarian cancer is the same as described supra. In certain embodiments the cervical cancer treated is metastatic cervical cancer. In certain embodiments, the cervical cancer treated is positive for HPV 16. In certain embodiments, the cervical cancer treated is positive for HPV 18. In certain embodiments, the cervical cancer treated is positive for HPV 16 and HPV 18. In certain embodiments, the cervical cancer treated is negative for HPV. In certain embodiments, the ovarian cancer treated is resistant to estrogen therapies. In certain embodiments, the ovarian cancer treated is resistant to anti-estrogen therapies. In certain embodiments, the anti-estrogen therapy is tamoxifen.
[00156] 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 entirety, as if fully set forth herein.
EXAMPLES
Example 1 : CC54 inhibited proliferation of cervical cancer cells and induced apoptosis of human cervical and ovarian cancer cells.
Methods
[00157] Detection of growth inhibition in HeLa and CaSki cervical cancer cells. Human cervical cancer cells (CaSki and HeLa) and normal control cells (human fibroblast and L929 mouse fibroblast) were grown to the logarithmic phase and seeded in 96-well plates. The plated cells were incubated at 37°C in a 5% C02 (v/v) humidified incubator overnight. Cells were then treated with various concentrations of CC54. After incubating the treated cells for 24 hours (Figures 1A and 2A), 48 hours (Figures 1 B, 2B and 3), and 72 hours (Figures 1 C and 2C), the cell growth inhibition rates and IC50 (μΜ) for the compound were determined. The CellTiter-Glo cell Luminescent Cell Viability assay kit from Promega (Madison, Wl) was used to determine cell viability according to the manufacturer's protocol. Cell growth inhibition rate was calculated using the following formula: Inhibition rate (%) = (1 - luminescence of test group / luminescence of DMSO control group) * 100%.
[00158] Detection of CC54 induced apoptosis of cervical and ovarian cancer cells by microscopy and flow cytometry. HeLa (HPV 18 positive), CaSki (HPV 16 and 18 positive), and C33A (HPV negative) human cervical cancer cells and SKOV3 (growth-resistant to estrogens and anti-estrogens) human ovarian cancer cells were grown to the logarithmic phase, plated as described above, and treated with different concentrations of CC54 for 48 hours. Annexin V/PI stained cells were observed by confocal laser scanning microscopy. Flow cytometry was used to detect the early and late apoptotic cells. The apoptotic index (Al) was calculated and it represented the percentage of apoptotic cells in the total cell population detected by microscopy or flow cytometry.
Results
[00159] CC54 significantly inhibited the growth of cervical cancer cells. CC54 significantly inhibited the growth of HeLa (Figures 1A-1 C) and CaSki cervical cancer cells (Figures 2A-2C) over different time points. In contrast, the human fibroblast and L929 mouse fibroblast cells serving as normal cell controls had a significantly lower sensitivity to CC54 than the CaSki and HeLa cervical cancer cell lines (Table 1 and Figure 3).
Table 1 . Inhibition of cervical cancer cell growth by CC54
Figure imgf000038_0001
[00160] CC54 induced apoptosis in cervical and ovarian cancer cells. CC54 induced apoptosis was detected by microscopy and flow cytometry. Flow cytometry data show the distribution of CC54 treated HeLa (Figure 4B), CaSki (Figure 5B), C33A (Figure 6B), and SKOV3 (Figure 7B) cells in different stages of apoptosis. HeLa, CaSki, C33A, and SKOV3 cells were treated with no solvent or DMSO only for the same time as controls, respectively (Figures 4A, 5A, 6A, and 7A). Tables 2-5 summarize the early, late, and total apoptotic indices determined from the microscopy and flow cytometry data for cervical cancer cells (HeLa, CaSki, and C33A) and ovarian cancer cells (SKOV3) treated with CC54.
[00161] The apoptotic index (Al) calculated by flow cytometry indicated that the treatment of the HeLa (Table 2), CaSki (Table 3), C33A (Table 4), and SKOV3 (Table 5) cells with CC54 for 48 hours exhibited a significant increase in apoptosis as the dosage of the compounds increased. CC54 induced apoptosis in HeLa (HPV 18 positive), CaSki (HPV 18 and 16 positive), and C33A (HPV negative) indicated that CC54 may inhibit the growth of cervical cancer cells that are HPV positive or negative (Tables 2-4). That CC54 induced apoptosis in the SKOV3 cells in a dose dependent manner suggests that those compounds also inhibited the growth of this ovarian cancer cell line (Table 5). Additionally, the data shows that CC54 inhibited the growth of ovarian cancer cells, such as SKOV3, that are growth-resistant to estrogen and anti-estrogens (Hua et. al., 1995).
Table 2. HeLa cell apoptotic indices with CC54 treatment
Figure imgf000039_0001
Table 3. CaSki cell apoptotic indices with CC54 treatment
Figure imgf000039_0002
Table 4. C33A cell apoptotic indices with CC54 treatment
Figure imgf000040_0001
Example 2: CC30 inhibited proliferation of cervical cancer cells and induced apoptosis of human cervical and ovarian cancer cells.
Methods
[00162] Detection of growth inhibition in HeLa and CaSki cervical cancer cells. Human cervical cancer cells (CaSki and HeLa) and normal control cells (human fibroblast and L929 mouse fibroblast) were grown to the logarithmic phase and seeded in 96-well plates. The plated cells were incubated at 37°C in a 5% C02 (v/v) humidified incubator overnight. Cells were then treated with various concentrations of CC30. After incubating the treated cells for 24 hours (Figures 8A and 9A), 48 hours (Figures 8B, 9B, and 10), or 72 hours (Figures 8C and 9C), the cell inhibition growth rate and IC50 (μΜ) for the compound were determined. The CellTiter-Glo cell Luminescent Cell Viability assay kit from Promega (Madison, Wl) was used to determine cell viability according to the manufacturer's protocol. Cell growth inhibition rate was calculated using the following formula: Inhibition rate (%) = (1 - Luminescence of test group / Luminescence of DMSO control group) * 100%.
[00163] Detection of CC30 induced apoptosis and growth inhibition for CaSki, SiHa, HeLa, and C4I cervical cancer cells. Human cervical cancer cells, CaSki (HPV16 positive), SiHa (HPV16 positive), HeLa (HPV18 positive), and C4I (HPV18 positive), were seeded according to the method described above. The cells were treated with CC30 having concentrations ranging from 5 μΜ to 20 μΜ. Cell viability and growth inhibition rates were determined as described above.
[00164] The activity of Caspase 3/7 (a pivotal effector caspases in the apoptotic pathway) was determined using the Caspase-Glo 3/7 assay kit from Promega (Madison, Wl) according to the manufacturer's protocol. The relative activity of Caspase 3/7 was calculated by the following formula: Caspase 3/7 activity (%) = luminescence of test group / luminescence of the DMSO control group * 100%.
[00165] Apoptosis of the CaSki cells was detected by Hoechest 33258 fluorescence staining. CaSki cells were treated with 20 μΜ CC30 for 48 hours and stained with 30μg/ml. Hoechst 33258 fluorescence dye was added at 37°C to a final concentration of 30 μg/ml. After staining for 1 hour in the dark at 37°C. Cells with bright, fragmented, condensed nuclei were identified as apoptotic cells using a fluorescence microscope. DMSO was used for the control group. The apoptotic rate was calculated by counting three to five random fields totaling at least 500 cells.
[00166] Detection of CC30 induced apoptosis of cervical and ovarian cancer cells by microscopy and flow cytometry. HeLa, CaSki, and C33A human cervical cancer cells and SKOV3 human ovarian cancer cells were grown to the logarithmic phase, plated as described above, and treated with different concentrations of CC30 for 48 hours. Annexin V/PI stained cells were observed by confocal laser scanning microscopy. Flow cytometry was used to detect the early and late apoptotic cells. The apoptosis index (Al) was calculated and it represented the percentage of apoptotic cells in the total cell population detected by microscopy or flow cytometry.
Results
[00167] CC30 significantly inhibited the growth of cervical cancer cells. CC30 significantly inhibited the growth of HeLa (Figures 8A-8C) and CaSki cervical cancer cells (Figures 9A-9C) at different time points. In contrast, the human fibroblast and L929 mouse fibroblast cells serving as normal cell controls had a significantly lower sensitivity to CC30 than the CaSki and HeLa cervical cancer cell lines (Table 6 and Figure 10).
Table 6. Inhibition of cervical cancer cell growth by CC30
Figure imgf000042_0001
[00168] Figure 1 1 shows that the cell proliferations were inhibited for all four cervical cancer cell lines (CaSki, SiHa, HeLa, and C4I) with the treatment of CC30 at the concentrations ranging from 5 μΜ to 20 μΜ. The increase in cell growth inhibition was proportional to the increased dose of treatment with CC30 (Figure 1 1 ). CC30 inhibited the cell growth of the cervical cancer cell lines in a dose dependent manner.
[00169] CC30 induced apoptosis in cervical and ovarian cancer cells. CC30 treatment induced a dose dependent increase of apoptosis in the different cervical cancer cell lines (CaSki, SiHa, HeLa, and C4I) (Figure 12). The apoptosis in the different cell types was observed as an increase in Caspase 3/7 cellular levels (Figure 12). Caspase 3/7 activity increased significantly more in HPV16-positive CaSki and SiHa cell lines in comparison to the HPV18-positive HeLa and C4I cell lines (Figure 12).
[00170] Additionally, Hoechest 33258 fluorescence staining demonstrated that CaSki cells treated with CC30 (20 μΜ) for 48 hours (Figure 13A) had a significantly higher apoptosis rate (57.6% ± 4.8%) than CaSki cells treated with DMSO (1 .5% ± 1 .2%; P < 0.01 , Figure 13B). The nuclei of the normal cells were round or oval with a uniform distribution of chromatin, while the nuclei of the apoptotic cells were bright blue due to the branched and fragmented chromatin that was concentrated at nuclei edges (Figures 13A-B).
[00171] CC30 induced apoptosis was also detected by microscopy and flow cytometry. Flow cytometry data showed the distribution of CC30 treated HeLa (Figure 14B), CaSki (Figure 15B), C33A (Figure 16B), and SKOV3 (Figure 17B) cells in different stages of apoptosis. HeLa, CaSki, C33A, and SKOV3 cells were treated with cell growth media or DMSO only for the same time as controls, respectively (Figures 14A, 15A, 16A, and 17A). Tables 7-10 summarize the early, late, and total apoptotic indices determined from the microscopy and flow cytometry data for cervical cancer cells (HeLa, CaSki, and C33A) and ovarian cancer cells (SKOV3) treated with CC30.
[00172] The apoptotic index (Al) calculated by flow cytometry indicated that the treatment of the HeLa (Table 7), CaSki (Table 8), C33A (Table 9), and SKOV3 (Table 10) cells with CC30 for 48 hours exhibited a significant increase in apoptosis as the dosage of the compounds increased. That CC30 induced apoptosis in the SKOV3 cells in a dose dependent manner suggests that those compounds also inhibited the growth of ovarian cancer cells (Table 10).
Table 7. HeLa cell apoptotic indices with CC30 treatment
Figure imgf000044_0001
Table 8. CaSki cell apoptotic indices with CC30 treatment
Figure imgf000044_0002
Table 9. C33A cell apoptotic indices with CC30 treatment
Figure imgf000045_0001
Example 3: CC30 significantly inhibited the growth of transplanted cervical cancer tumors in BALB/c nude mice and SCID mice. Methods
[00173] Tumor transplantation and treatment of BALB/c nude mice. Female BALB/c nu/nu nude mice that were 4-5 weeks old and had an average weight of 18.06 ± 0.72 grams were used in the experiment. The mice were fed under specific pathogen free (SP) conditions. Food and water were available to the mice at will. Ten BALB/c nude mice were randomly divided into two groups as the CC30 treated group and the solvent control group with five mice in each group. A suspension of 5 x 106 cells per mouse CaSki cells (0.2 ml.) in logarithmic phase were innoculated subcutaneously into the right back of the BALB/c nude mice.
[00174] The general conditions of the mice and the growth of the transplanted tumor were monitored. After 1 week when the transplanted tumor grew to 0.3-0.5 cm in diameter, the treated group received an intraperitoneal injection of CC30 (200 μΙ_ volume; 50 mg/kg) once a day, 5 times a week, and for 5 weeks. The control group received an intraperitoneal injection of the solvent (20% DMSO, 80% of 20% w/v (2-Hydroxypropyl)-3-cyclodextrin made in PBS).
[00175] The body weights of the mice were recorded prior to the start of the 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 done every 2 days to estimate the tumor volume; the following formula: 4π/3 * (width/2 )2 χ (length/2) was used to calculate the three-dimensional volume of an ellipse. The growth curve was drawn according to the tumor volume. The tumor inhibition rate was calculated according to tumor volume: Tumor inhibition rate (%) = (Tumor volume of the control group - tumor volume of the treated group) / Tumor volume of the control group χ 100%.
[00176] The BALB/c nude mice were euthanized - if weight loss was more than 20% or the tumor diameter reached 1 .5 cm during the experiment. The BALB/c nude mice were euthanized on the next day after the final injection. Tumor and vital organs, such as liver, kidney and spleen, from each mouse were carefully dissected out, weighed, and divided into two parts. One piece was fixed in 10% buffered formalin and used for histopathology or immunohistochemistry. The second piece was snap frozen in liquid nitrogen and stored at -80°C. Paraffin sections were routinely stained with hematoxylin - eosin (HE). The pathological changes of the transplanted tumor, liver and kidney were observed under an optical microscope.
[00177] Tumor transplantation and treatment of SCID mice. CaSki cervical cancer cells were transplanted into CB1 severe combined immunodeficiency (SCID) female mice and treated with CC30 using the same experimental method and treatment protocol as described above for the BALB/c nude mice. All experimental procedures were the same as described above except that the SCID mice were euthanized 26 days rather than 40 days after treatment. The transplanted tumors in the control group of SCID mice grew to a diameter greater than 1 .5 cm by day 26 and had to be sacrificed at the earlier time point.
Results
[00178] CC30 inhibited the growth of transplanted tumors in BABUc mice. One week after seeding the BALB/c nude mice with CaSki cells, all of the transplanted tumors grew to a diameter of approximately 0.3-0.5 cm. The rate of successful transplantation was 100%. After 5 weeks treatment with CC30, the tumor volume of the control group was 639.37 ± 329.28 mm3, while the tumor volume of the CC30 treated group was 88.14 ± 96.57 mm3 (Table 1 1 ). The tumor inhibition rate of the treated group was 85% compared to the control group. The tumor weight was significantly less than that of the control group, and the difference was statistically significant (Figure 18 and Table 1 1 ). Table 11. Body weight and tumor size of BABL/c nude mice with transplanted cervical cancer tumors
Figure imgf000048_0001
[00179] Moreover, metastases appeared in 1 of the control BALB/c nude mice. The in-vivo findings demonstrated that CC30 significantly inhibited the growth of CaSki tumors in mice. No apparent changes in body weight, behavior, activity or posture, areas of redness and swelling, and food and water withdrawal, were observed in the CC30 treated group. The morphology and organizational structure of liver and kidney in the CC30 appeared normal by HE staining in the CC30 treated group. No inflammatory cell infiltration on liver cells, no denaturation, hemorrhage and necrosis, and no central venous expansion were observed in the CC30 treated mice. Also, no proliferation, hemorrhage and necrosis in glomerulus epithelial, no inflammatory cell infiltration on kidney tubules, no denaturation, hemorrhage and necrosis was observed in the CC30 treated mice. These results demonstrate that the BALB/c nude mice tolerated the intraperitoneal injection of CC30 at 50 mg/kg/d.
[00180] Morphological differences in the extracted tumors from the CC30 treated and the control groups were observed. Transplanted tumors are generally nodular and movable. Observing through the optical microscope, the tumor cells of the control group were in a disordered arrangement and had a highly atypical morphology. The control group tumors were of different sizes and irregular forms. Also, the control group tumors had deeply stained multiple nuclei and were in the mitosis phase as commonly observed in such cells. In contrast, the tumors from the treated group had a decrease in volume and a reduced number of cells in the mitosis phase, which is relatively less common.
[00181 ] CC30 inhibited the growth of transplanted tumors in SCID mice. One week after the SCID mice were seeded with CaSki cells, all of the transplanted tumors on the SCID mice grew to a diameter of approximate 0.5-0.7 cm. The success rate of transplantation was 100%. After 26 days of treatment with CC30, the tumor volume of the control group was 799.63 ± 167.56 mm3, and the tumor volume of the CC30 treated group was 415.37 ± 146.03 mm3 (Table 12). Compared to the control group, the tumor inhibition rate of the CC30 treated group was approximately 50%. The tumor weight of the CC30 treated group was significantly less than that of the control group, and the difference was statistically significant (Figure 19 and Table 12).
Table 12. Body weight and tumor size of SCID mice with transplanted cervical cancer tumors
Figure imgf000049_0001
[00182] Moreover, metastases also appeared on one SCID mouse from the control group. These results demonstrated that CC30 can significantly inhibit the growth of cervical cancer tumors transplanted into SCID mice. General conditions of the CC30 treated group of SCID mice, such as mental state and body weight, did not change during treatment.
Example 4: CC30 significantly inhibited the growth of HeLa transplanted tumors in BALB/c nude mice.
Methods
[00183] BALB/c nu/nu nude mice, 4-5 weeks old, female, were fed under SPF (specific pathogen free) conditions. Food and water were available to mice at will. Twenty-five BALB/c nude mice were randomly divided into 3 subgroups with 5 mice per group: intraperitoneal injection (IP) solvent control group, IP CC30 treatment group, and oral cisplatin treatment group.
[00184] HeLa cells (200 μΙ) in logarithmic phase were seeded subcutaneously on the right back of the nude mice (about 3 * 06 cells for each mouse). The general conditions of the mice and the growth of the transplanted tumor were observed. When the transplanted tumor grew to 0.3-0.5 cm in diameter after 1 week, the IP CC30 treatment group was intraperitoneally injected with 50mg/KG (injection volume 200uL) of CC30, once a day, 5 times a week, while the IP control group was injected intraperitoneally with 200 μί of solvent (20% DMSO, 20% w/v (2-Hydroxypropyl)-3- cyclodextrin made by 80% PBS), following the same administration schedule. The cisplatin treatment group was gavaged with 5 mg/kg of cisplatin once per week and served as a positive control to ensure the validity of the model.
[00185] The body weights of mice were measured at least twice a week and the total dose was adjusted according to body weight. The major axis (a) and minor axis (b) were measured with sliding calipers at least twice a week, and the tumor volume was calculated according to the following formula: Volume (V) = 4π/3 * (b/2)2 (a/2)
[00186] Nude mice were sacrificed if the body weight decreased by more than 20% or tumor diameter was more than 1 .5 cm during the experiment. On the next day after final administration, the subcutaneous tumor nodules were taken out intact and weighed. T/C % was calculated according to tumor weights: T/C % = (Tumor weight of treatment group / Tumor weight of control group with same mode of administration) X 100.
Results
[00187] The successful rate of the transplantation was 100% as all tumors grew to approximately 0.3-0.5 cm in diameter one week after HeLa cell inoculation. After 4 weeks of treatment, tumor size was significantly reduced for the cisplatin treatment group, indicating that the model was valid as the tumor reacted to cisplatin treatment as expected (Table 13). CC30 significantly inhibited growth of the transplanted tumor when injected intraperitoneally (Table 13 and Figure 20). Figure 20 shows the significantly smaller tumors that were extracted from the mice in the IP CC30 treatment group as compared to those extracted from the IP control group (Figure 20). Table 13. CC30 inhibited the growth of tumors in BALB/c nude mice transplanted with HeLa cervical cancer cells
Figure imgf000052_0001
REFERENCES
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.
1 . Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. (2010) Int J Cancer.127(12):2893-2917.
2. Candelaria, M., Garcia-Arias, A., Cetina, L, Duenas-Gonzalez, A.
Radiosensitizers in cervical cancer. Cisplatin and beyond. (2006) Radiation Oncology 1: 15.
3. Scatchard K, Forrest JL, Flubacher M, Cornes P, Williams C. Chemotherapy for metastatic and recurrent cervical cancer. Cochrane Database of
Systematic Reviews 2012, Issue 10. Art. No.: CD006469. DOI:
10.1002/14651858.CD006469.pub2.
4. Physician's Desk Reference, 41 st Ed., Publisher Edward R. Barnhart, N.J.
(1987).
5. PCT/US93/0082948.
6. Remington: The Science and Practice of Pharmacy, 21 st Edition, Univ. of Sciences in Philadelphia (USIP), Lippincott Williams & Wilkins, Philadelphia, PA, 2005.
7. Hua, W., Christianson, T., Rougeot, C, Rochefort, H., and Clinton, G.M.
SKOV3 ovarian carcinoma cells have functional estrogen receptor but are growth-resistant to estrogen and antiestrogens. (1995) J. Steroid Biochem. Mol. Biol. 55(3-4): 279-289.

Claims

CLAIMS What is claimed is:
1 . A method of treating cervical cancer and/or ovarian cancer in a subject comprising administering to the subject a therapeutically effective amount of one or more transcription factor modulators, wherein the one or more transcription factor modulators comprise a structure selected from the group consisting of a structure selected from the group consisting of CC54, CC30, Structure I, Structure II,
Structure IMA, Structure NIB, Structure NIC, Structure IVA, Structure IVB, Structure IVC, Structure IVD, Structure VIIA, Structure VIIB, Structure VIIC, Structure VIID, Structure VIIE, Structure VIII, Formula I, Formula II, Formula IIIA, Formula NIB, Formula NIC, Formula IVA, Formula IVB, Formula IVC, Formula IVD, Formula VIIA, Formula VI IB, Formula VIIC, Formula VIID, Formula VIIE, and Formula VIII, including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, and further including mixtures thereof in all ratios, 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, alkyl, and haloalkyi, wherein at least one or two of R1-R5 are halogen and/or haloalkyi;
Xi and X2 are independently selected from -NHC(=0)- or -C(=0)-NH-;
Li 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 -0-, -S-, -C(=0)-, -S(=0)-, -S(=0)2-, -NH-C(=0)-, -C(=0)-NH-, -NR-, - C=C-, carbon-carbon triple bond, phenylene, 1 , 4-phenylene and cyclohexylene, 1 , 4-cyclohexylene, wherein R is hydrogen, alkyl or aryl;
Ai and Bi rings are each independently selected from the group consisting of phenyl, pyridyl and N-alkylated pyridyl rings;
Rn-R-15 are each independently selected from the group consisting of hydrogen, halogen and alkyl, wherein one or two of R11-R15 are halogens;
X11 and X-12 are each independently selected from -NHC(=0)- or -C(=0)-NH-;
L-i-i is -(CH2)nr, where n-ι is 4, 5, 6, 7, or 8, optionally wherein one or more - CH2- moieties are replaced with one or more substituents selected from the group consisting of -O-, -S-, -C(=0)-, -S(=0)-, -S(=0)2-, -NH-C(=0)-, -C(=0)-NH-, -NR18-, - C=C-, carbon-carbon triple bond, phenylene and cyclohexylene; and
R-I8 is hydrogen, alkyl or aryl.
2. The method according to claim 1 , wherein the cervical cancer treated is metastatic cervical cancer.
3. The method according to claim 1 , wherein the cervical cancer treated is positive for HPV 16.
4. The method according to claim 1 , wherein the cervical cancer treated is positive for HPV 18.
5. The method according to claim 1 , wherein the cervical cancer treated is positive for HPV 16 and HPV 18.
6. The method according to claim 1 , wherein the cervical cancer treated is negative for HPV.
7. The method according to claim 1 , wherein the ovarian cancer is resistant to anti-estrogen therapies.
8. The method according to claim 6, wherein the anti-estrogen therapy is tamoxifen.
9. A method of treating cervical and/or ovarian cancer in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising one or more transcription factor modulators, wherein the one or more transcription factor modulators comprise a structure selected from the group consisting of a structure selected from the group consisting of CC54, CC30,
Structure I, Structure II, Structure MA, Structure NIB, Structure NIC, Structure IVA, Structure IVB, Structure IVC, Structure IVD, Structure VIIA, Structure VI IB, Structure VIIC, Structure VI ID, Structure VIIE, Structure VIII, Formula I, Formula II, Formula MA, Formula MB, Formula NIC, Formula IVA, Formula IVB, Formula IVC, Formula IVD, Formula VIIA, Formula VIIB, Formula VIIC, Formula VIID, Formula VI IE, and Formula VII I, including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, and further including mixtures thereof in all ratios, 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, alkyl, and haloalkyi, wherein at least one or two of R1-R5 are halogen and/or haloalkyi; Xi and X2 are independently selected from -NHC(=0)- or -C(=0)-NH-;
Li 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 -0-, -S-, -C(=0)-, -S(=0)-, -S(=0)2-, -NH-C(=0)-, -C(=0)-NH-, -NR-, - C=C-, carbon-carbon triple bond, phenylene, 1 , 4-phenylene and cyclohexylene, 1 , 4-cyclohexylene, wherein R is hydrogen, alkyl or aryl;
Ai and Bi rings are each independently selected from the group consisting of phenyl, pyridyl and N-alkylated pyridyl rings;
Rn-R-15 are each independently selected from the group consisting of hydrogen, halogen and alkyl, wherein one or two of R11-R15 are halogens;
X11 and Xi2 are each independently selected from -NHC(=0)- or -C(=0)-NH-;
L-i -i is -(CH2)nr, where n-ι is 4, 5, 6, 7, or 8, optionally wherein one or more - CH2- moieties are replaced with one or more substituents selected from the group consisting of -O-, -S-, -C(=0)-, -S(=0)-, -S(=0)2-, -NH-C(=0)-, -C(=0)-NH-, -NR18-, - C=C-, carbon-carbon triple bond, phenylene and cyclohexylene; and
R-I8 is hydrogen, alkyl or aryl.
10. The method according to claim 9, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
1 1 . The method according to claim 9, wherein the cervical cancer treated is metastatic cervical cancer.
12. The method according to claim 9, wherein the cervical cancer treated is positive for HPV 16.
13. The method according to claim 9, wherein the cervical cancer treated is positive for HPV 18.
14. The method according to claim 9, wherein the cervical cancer treated is positive for HPV 16 and HPV 18.
15. The method according to claim 9, wherein the cervical cancer treated is negative for HPV.
16. The method according to claim 9, wherein the ovarian cancer is resistant to anti-estrogen therapies.
17. The method according to claim 16, wherein the anti-estrogen therapy is tamoxifen.
PCT/US2014/021451 2013-03-06 2014-03-06 Treatment of cervical cancer and/or ovarian cancer using a transcription factor modulator WO2014138507A1 (en)

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