WO2014134800A1

WO2014134800A1 - Treatment of cervical cancer and/or ovarian cancer using transcription factor modulator

Info

Publication number: WO2014134800A1
Application number: PCT/CN2013/072247
Authority: WO
Inventors: Lin Chen; Xiaojiang Chen; Guangshi TAO; Meng XIA; Dahai GAI
Original assignee: Tianshu Biotechnology. Ltd; C&C Biopharma, Llc
Priority date: 2013-03-06
Filing date: 2013-03-06
Publication date: 2014-09-12
Also published as: WO2014134840A1

Abstract

In certain embodiments, 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

TRANSCRIPTION FACTOR MODULATOR

BACKGROUND

[0001] Cervical cancer is the third most common cancer afflicting women, with an estimated 530,000 new cases and 275,000 deaths each year (Ferlay et. al., 2010), and also the most deadly. 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 the lack of efficient identification methods at early stages and the high tendency of metastasis.

[0002] 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). However, cure rates using these treatment options are low, with an effective rate of only 30-50% (Scatchard et al., 2012).

Further, these chemotherapeutic drugs are generally very toxic and can have severe adverse side effects on general health and life quality of patients. Chemotherapy drugs such as cisplatin and carboplatin may 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.

[0003] 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

[0004] 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.

[0005] 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

[0006] Figure 1 - Dose dependent growth inhibition of HeLa cells by Compound 1 . (A) Effects of Compound 1 after treatment of 24 hours; (B) Effects of Compound 1 after treatment of 48 hours; and (C) Effects of Compound 1 after treatment of 72 hours.

[0007] Figure 2 - Dose dependent growth inhibition of CaSki cells by Compound 1 . (A) Effects of Compound 1 after treatment of 24 hours; (B) Effects of Compound 1 after treatment of 48 hours; and (C) Effects of Compound 1 after treatment of 72 hours.

[0008] Figure 3 - Dose dependent growth inhibition of L292 cells by Compound 1 after treatment of 48 hours.

[0009] Figure 4 - Flow cytometry data showing Compound 1 induced early and late 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 Compound 1 (10 μΜ~40 μΜ).

[0010] Figure 5 - Flow cytometry data showing Compound 1 induced early and late 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 Compound 1 (10 μΜ~40 μΜ).

[0011] Figure 6 - Flow cytometry data showing Compound 1 induced early and late 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 Compound 1 (10 μΜ~40 μΜ).

[0012] Figure 7 - Flow cytometry data showing Compound 1 induced early and late 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 Compound 1 (10 μΜ~40 μΜ).

DETAILED DESCRIPTION

[0013] 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.

[0014] 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 ovarian cancer treated is resistant to anti-estrogen therapies. In certain embodiments, the anti-estrogen therapy is tamoxifen.

[0015] /. Transcription factor modulators

[0016] The one or more transcription factor modulators disclosed herein comprise a structure of Compound 1 :

Compound 1 , including pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers thereof, further including mixtures thereof in all ratios.

[0017] 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.

[0018] 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.

[0019] 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. Compound 1 ). 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.

[0020] 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 the Compound 1 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 Compound 1 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 Compound 1 are included within the scope of the structure of Compound 1 and preferably the structures corresponding thereto.

[0021] 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.

[0022] 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.

[0023] //. Pharmaceutical compositions

[0024] As used herein, a pharmaceutical composition comprises a therapeutically effective amount of one or more transcription factor modulators disclosed herein (e.g. Compound 1 ). In certain embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0025] 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.

[0026] 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. Compound 1 ) 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.

[0027] As used herein, the term "about" refers to ±10%, ±5%, or ±1 %, of the value following "about." [0028] 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.

[0029] 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 non-toxic compatible substances employed in pharmaceutical formulations.

[0030] 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.

[0031] The concentration of the one or more transcription factor modulators disclosed herein (e.g. Compound 1 ) 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.

[0032] 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.

[0033] One skilled in the art will recognize that a pharmaceutical composition containing the one or more transcription factor modulators disclosed herein (e.g.

Compound 1 ) 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.

[0034] 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.

[0035] 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. Compound 1 ). 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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). [0040] ///. Methods of treating

[0041] 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.

[0042] "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.

[0043] In certain embodiments, the one or more transcription factor modulators disclosed herein (e.g. Compound 1 ) are administered in combination with a therapeutic agent or radiotherapy.

[0044] 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. 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 ovarian cancer treated is resistant to anti-estrogen therapies. In certain embodiments, the anti-estrogen therapy is tamoxifen.

[0045] 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 : Compound 1 inhibited proliferation of cervical cancer cells and induced apoptosis of human cervical and ovarian cancer cells.

Methods

[0046] 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% CO₂ (v/v) humidified incubator overnight. Cells were then treated with various concentrations of Compound 1 . After incubating the treated cells for 24 hours (Figures 1 A 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%.

[0047] Detection of Compound 1 induced apoptosis of cervical and ovarian cancer cells by microscopy and flow cytometry. HeLa, CaSki, and C33A human cervical cancer cells and SK0V3 human ovarian cancer cells were grown to the logarithmic phase, plated as described above, and treated with different concentrations of Compound 1 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

[0048] Compound 1 significantly inhibited the growth of cervical cancer cells. Compound 1 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 Compound 1 than the CaSki and HeLa cervical cancer cell lines (Table 1 and Figure 3).

Table 1. Inhibition of cervical cancer cell growth by Compound 1

[0049] Compound 1 induced apoptosis in cervical and ovarian cancer cells. Compound 1 induced apoptosis was detected by microscopy and flow cytometry. Flow cytometry data show the distribution of Compound 1 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 Compound 1 .

[0050] The apoptotic index (Al) calculated by flow cytometry indicated that the treatment of the HeLa (see Table 2), CaSki (see Table 3), C33A (see Table 4), and SKOV3 (see Table 5) cells with Compound 1 for 48 hours exhibited a significant increase in apoptosis as the dosage of the compounds increased. That Compound 1 induced apoptosis in the SKOV3 cells in a dose dependent manner suggests that those compounds also inhibit the growth of this ovarian cancer cell line (Table 5).

Table 2. HeLa cell apoptotic indices with Compound 1 treatment

Table 3. CaSki cell apoptotic indices with Compound 1 treatment

Table 5. Skov3 cell apoptotic indices with Compound 1 treatment Compound 1 Early Late Total

Compound Concentration Apoptotic Apoptotic Apoptotic Treated

(μΜ) Index Index Index

(±s) (±s) (±s)

No solvent 0 5.8±0.9 4.3±1.0 10.0±1.8

DMSO 0 7.7±1.1 5.6±1.0 13.3±0.5

10 6.6±0.7 7.8±0.8 14.4±0.9

20 9.2±1.5 21.6±2.0 30.8±3.4

Compound 1

30 7.2±0.7 24.2±2.2 32.1 ±1 .9

40 13.8±2.5 55.2±3.5 69.0±5.56

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 entirety, 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. Physician's Desk Reference, 41 st Ed., Publisher Edward R. Barnhart, N.J.

(1987).

PCT/US93/0082948.

Remington: The Science and Practice of Pharmacy, 21 st Edition, Univ. of Sciences in Philadelphia (USIP), Lippincott Williams & Wilkins, Philadelphia, PA, 2005.

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 of Compound 1 :

Compound 1 ,

or pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof.

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 ovarian cancer is resistant to anti- estrogen therapies.

7. The method according to claim 6, wherein the anti-estrogen therapy is tamoxifen.

8. 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 of Compound 1 :

Compound 1 , or pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof.

9. The method according to claim 8, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

10. The method according to claim 8, wherein the cervical cancer treated is metastatic cervical cancer.

1 1. The method according to claim 8, wherein the cervical cancer treated is positive for HPV 16.

12. The method according to claim 8, wherein the cervical cancer treated is positive for HPV 18.

13. The method according to claim 8, wherein the cervical cancer treated is positive for HPV 16 and HPV 18.

14. The method according to claim 8, wherein the ovarian cancer is resistant to anti- estrogen therapies.

15. The method according to claim 14, wherein the anti-estrogen therapy is tamoxifen.