WO2018195202A1 - Compositions and methods for the treatment of cancer - Google Patents

Compositions and methods for the treatment of cancer Download PDF

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Publication number
WO2018195202A1
WO2018195202A1 PCT/US2018/028172 US2018028172W WO2018195202A1 WO 2018195202 A1 WO2018195202 A1 WO 2018195202A1 US 2018028172 W US2018028172 W US 2018028172W WO 2018195202 A1 WO2018195202 A1 WO 2018195202A1
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Prior art keywords
formula
compound
product combination
agent
hydrogen
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PCT/US2018/028172
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French (fr)
Inventor
Per BORGSTRÖM
Veronique Therese BARON
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Pellficure Pharmaceuticals Inc.
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Publication of WO2018195202A1 publication Critical patent/WO2018195202A1/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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present disclosure relates to methods and compositions for treating, inhibiting, or ameliorating diseases and/or conditions associated with a cancer, such as prostate cancer or bladder cancer.
  • the present disclosure relates to pharmaceutical compositions including naphthoquinone analogs and methods of using these compounds alone or in combination with additional compounds, including androgen deprivation agents, taxane-based chemotherapy agents, and/or platinum-based antineoplastic agents, for treating, ameliorating, or inhibiting a disease and/or condition associated with a cancer, such as prostate cancer or bladder cancer.
  • the disclosure also relates to combination therapeutics and therapies, including naphthoquinone analogs provided in combination with an androgen deprivation agents, taxane-based chemotherapy agents, and/or platinum-based antineoplastic agents, for treating, ameliorating, or inhibiting a disease and/or condition associated with a cancer, such as prostate cancer or bladder cancer, with said combination therapeutic and therapies.
  • combination therapeutics and therapies including naphthoquinone analogs provided in combination with an androgen deprivation agents, taxane-based chemotherapy agents, and/or platinum-based antineoplastic agents, for treating, ameliorating, or inhibiting a disease and/or condition associated with a cancer, such as prostate cancer or bladder cancer, with said combination therapeutic and therapies.
  • the androgen receptor (“AR”) is a ligand-activated transcriptional regulatory protein that mediates induction of a variety of biological effects through its interaction with endogenous androgens.
  • Endogenous androgens include steroids such as testosterone and dihydrotestosterone.
  • Testosterone is converted to dihydrotestosterone by the enzyme 5 alpha-reductase in many tissues.
  • bladder cancer accounted for 74,000 new cases and 16,000 deaths in the USA in 2015, and 165,000 deaths worldwide.
  • Urothelial cell carcinomas of the bladder are classified into two categories termed non-muscle invasive bladder cancer and muscle invasive bladder cancer.
  • Non-muscle invasive bladder cancer is highly treatable, usually by complete resection of the tumor followed by immunotherapy with intra-vesical BCG vaccine or intra-vesical chemotherapy.
  • Advanced bladder cancer is difficult to treat and up to 50%> of patients receiving drugs infused into the bladder (intravesical agents) will experience recurrence of the cancer.
  • Advanced metastatic disease is usually treated by radical cystectomy together with neoadjuvant chemotherapy: methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or gemcitabine and cisplatin (GC). Kim, Curr Urol Rep, 2012, 13, 147-152.
  • MVAC methotrexate
  • doxorubicin doxorubicin
  • GC gemcitabine and cisplatin
  • Metastatic cancer although treated aggressively, has dismal survival rates with a median survival time of 15 months (9 months for refractory patients) and a 5-year survival rate of 15% (Oing et al. J Urol, 2016, 195, 254-263).
  • Prostate cancer develops in the prostate and is typically slow growing; however, some prostate cancers are aggressive. Prostate cancer cells are typically androgen/testosterone/DHT dependent and may metastasize from the prostate to other parts of the body, particularly the bones and lymph nodes. Treatment options for prostate cancer that remains within the prostate include watchful waiting/active surveillance, external beam radiation therapy, brachytherapy, cryosurgery, high-intensity focused ultrasound (HIFU), and surgery. Hormonal therapy and chemotherapy are often reserved for disease that has spread beyond the prostate. However, there are exceptions in that radiation therapy may be used for some advanced tumors, and hormonal therapy may be used for some early stage tumors.
  • prostate cancer cells resume growth despite the androgen/testosterone/DHT blockade.
  • hormone-refractory prostate cancer or “androgen-independent prostate cancer”
  • castration-resistant prostate cancer CRPC
  • Chemotherapeutic agents and immunotherapy have been shown to prolong survival after CRPC but the survival benefit is limited.
  • the need for more cancer treatments, in particular bladder cancer and prostate cancer treatments is manifest.
  • the product combination comprises: a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
  • the product combination further comprises a therapeutically effective amount of a taxane-based chemotherapy agent.
  • the taxane-based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof.
  • the compound of Formula (I) is present in an amount of 0.1 ⁇ to 10 ⁇ , such as 0.1 ⁇ , 0.5 ⁇ , 1.0 ⁇ , 1.5 ⁇ , 2 .0 ⁇ , 2.5 ⁇ , 3.0 ⁇ , 3.5 ⁇ , 4.0 ⁇ , 4.5 ⁇ , 5.0 ⁇ , 5.5 ⁇ , 6.0 ⁇ , 6.5 ⁇ , 7.0 ⁇ , 7.5 ⁇ , 8.0 ⁇ , 8.5 ⁇ , 9.0 ⁇ , 9.5 ⁇ , or 10.0 ⁇ or within a range defined by any two of the aforementioned amounts.
  • the taxane-based chemotherapy agent is present in an amount of 0.1 ⁇ to 10 ⁇ , such as 0.1 ⁇ , 0.5 ⁇ , 1.0 ⁇ , 1.5 ⁇ , 2 .0 ⁇ , 2.5 ⁇ , 3.0 ⁇ , 3.5 ⁇ , 4.0 ⁇ , 4.5 ⁇ , 5.0 ⁇ , 5.5 ⁇ , 6.0 ⁇ , 6.5 ⁇ , 7.0 ⁇ , 7.5 ⁇ , 8.0 ⁇ , 8.5 ⁇ , 9.0 ⁇ , 9.5 ⁇ , or 10.0 ⁇ or within a range defined by any two of the aforementioned amounts.
  • said product combination inhibits the growth of prostate cancer.
  • said product combination inhibits or delays the onset of castration-resistant prostate cancer.
  • the compound of Formula (I) is formulated for oral or parenteral administration.
  • the taxane-based chemotherapy agent is formulated for oral or parenteral administration.
  • the compound of Formula (I) and the taxane-based chemotherapy agent are provided to a subject in a single formulation or a single dosage.
  • the compound of Formula (I) and the taxane-based chemotherapy agent are formulated for oral or parenteral administration.
  • said prostate cancer is androgen dependent prostate cancer.
  • said prostate cancer is castration-resistant prostate cancer.
  • the product combination reduces prostate cancer tumor size.
  • the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a taxane-based chemotherapy agent.
  • the prostate cancer is inhibited or treated.
  • said method inhibits the growth of prostate cancer. In some embodiments, said method inhibits or delays the onset of castration-resistant prostate cancer.
  • the taxane-based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof.
  • the compound of Formula (I) is administered to the subject orally or parenterally.
  • the taxane-based chemotherapy agent is administered to the subject orally or parenterally.
  • the compound of Formula (I) and the taxane-based chemotherapy agent are administered to the subject orally or parenterally.
  • said prostate cancer is androgen dependent prostate cancer.
  • said prostate cancer is castration-resistant prostate cancer.
  • prostate cancer tumor size is reduced.
  • the product combination comprises: a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
  • the product combination further comprises a therapeutically effective amount of a platinum-based antineoplastic agent.
  • the platinum-based antineoplastic agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, or satraplatin, or analogues or derivatives thereof.
  • the compound of Formula (I) is present in an amount of 0.1 ⁇ to 10 ⁇ , such as 0.1 ⁇ , 0.5 ⁇ , 1.0 ⁇ , 1.5 ⁇ , 2 .0 ⁇ , 2.5 ⁇ , 3.0 ⁇ , 3.5 ⁇ , 4.0 ⁇ , 4.5 ⁇ , 5.0 ⁇ , 5.5 ⁇ , 6.0 ⁇ , 6.5 ⁇ , 7.0 ⁇ , 7.5 ⁇ , 8.0 ⁇ , 8.5 ⁇ , 9.0 ⁇ , 9.5 ⁇ , or 10.0 ⁇ or within a range defined by any two of the aforementioned amounts and wherein the platinum-based antineoplastic agent is present in an amount of 0.1 ⁇ to 10 ⁇ , such as 0.1 ⁇ , 0.5 ⁇ , 1.0 ⁇ , 1.5 ⁇ , 2 .0 ⁇ , 2.5 ⁇ , 3.0 ⁇ , 3.5 ⁇ , 4.0 ⁇ , 4.5 ⁇ , 5.0 ⁇ , 5.5 ⁇ , 6.0 ⁇ , 6.5 ⁇ , 7.0 ⁇ , 7.5
  • said product combination inhibits the growth of prostate cancer. In some embodiments, said product combination inhibits or delays the onset of castration-resistant prostate cancer. In some embodiments, the compound of Formula (I) is formulated for oral or parenteral administration. In some embodiments, the platinum-based antineoplastic agent is formulated for oral or parenteral administration. In some embodiments, the compound of Formula (I) and the platinum -based antineoplastic agent are provided to a subject in a single formulation or a single dosage. In some embodiments, the compound of Formula (I) and the platinum-based antineoplastic agent are formulated for oral or parenteral administration. In some embodiments, said prostate cancer is androgen dependent prostate cancer. In some embodiments, said prostate cancer is castration-resistant prostate cancer. In some embodiments, the product combination reduces prostate cancer tumor size.
  • Some embodiments provided herein relate to a method of inhibiting or treating prostate cancer.
  • the method comprises administering to a subject having prostate cancer a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
  • the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a platinum-based antineoplastic agent.
  • the prostate cancer is inhibited or treated.
  • said method inhibits the growth of prostate cancer. In some embodiments, said method inhibits or delays the onset of castration-resistant prostate cancer.
  • the platinum-based antineoplastic agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, or satraplatin, or analogues or derivatives thereof.
  • the compound of Formula (I) is administered to the subject orally or parenterally. In some embodiments, the platinum-based antineoplastic agent is administered to the subject orally or parenterally.
  • the compound of Formula (I) and the platinum-based antineoplastic agent are administered to the subject orally or parenterally.
  • said prostate cancer is androgen dependent prostate cancer.
  • said prostate cancer is castration-resistant prostate cancer.
  • the prostate cancer tumor size is reduced.
  • the product combination comprises: a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
  • the product combination further comprises a therapeutically effective amount of a taxane-based chemotherapy agent.
  • the taxane-based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof.
  • the compound of Formula (I) is present in an amount of 0.1 ⁇ to 10 ⁇ , such as 0.1 ⁇ , 0.5 ⁇ , 1.0 ⁇ , 1.5 ⁇ , 2 .0 ⁇ , 2.5 ⁇ , 3.0 ⁇ , 3.5 ⁇ , 4.0 ⁇ , 4.5 ⁇ , 5.0 ⁇ , 5.5 ⁇ , 6.0 ⁇ , 6.5 ⁇ , 7.0 ⁇ , 7.5 ⁇ , 8.0 ⁇ , 8.5 ⁇ , 9.0 ⁇ , 9.5 ⁇ , or 10.0 ⁇ or within a range defined by any two of the aforementioned amounts, and wherein the taxane-based chemotherapy agent is present in an amount of 0.1 ⁇ to 10 ⁇ , such as 0.1 ⁇ , 0.5 ⁇ , 1.0 ⁇ , 1.5 ⁇ , 2 .0 ⁇ , 2.5 ⁇ , 3.0 ⁇ , 3.5 ⁇ , 4.0 ⁇ , 4.5 ⁇ , 5.0 ⁇ , 5.5 ⁇ , 6.0 ⁇ , 6.5 ⁇ , 7.0 ⁇ , 7.5
  • said product combination inhibits the growth of bladder cancer.
  • the compound of Formula (I) is formulated for oral or parenteral administration.
  • the taxane-based chemotherapy agent is formulated for oral or parenteral administration.
  • the compound of Formula (I) and the taxane-based chemotherapy agent are provided to a subject in a single formulation or a single dosage.
  • the compound of Formula (I) and the taxane-based chemotherapy agent are formulated for oral or parenteral administration.
  • the product combination reduces bladder cancer tumor size.
  • Some embodiments provided herein relate to a method of inhibiting or delaying the growth of bladder cancer in a subject.
  • the method comprises administering to a subject having bladder cancer a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
  • the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a taxane-based chemotherapy agent.
  • the bladder cancer is inhibited or treated.
  • the bladder cancer comprises transitional cell carcinoma, squamous cell carcinoma, and/or adenocarcinomas of the bladder.
  • said method inhibits the growth of bladder cancer.
  • said method inhibits or delays the onset of bladder cancer.
  • the taxane- based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof.
  • the compound of Formula (I) is administered to the subject orally or parenterally.
  • the taxane-based chemotherapy agent is administered to the subject orally or parenterally. In some embodiments, the compound of Formula (I) and the taxane-based chemotherapy agent are administered to the subject orally or parenterally. In some embodiments, the bladder cancer tumor size is reduced.
  • the product combination comprises: a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
  • the product combination further comprises a therapeutically effective amount of a platinum-based antineoplastic agent.
  • the platinum-based antineoplastic agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, or satraplatin, or analogues or derivatives thereof.
  • the compound of Formula (I) is present in an amount of 0.1 ⁇ to 10 ⁇ , such as 0.1 ⁇ , 0.5 ⁇ , 1.0 ⁇ , 1.5 ⁇ , 2 .0 ⁇ , 2.5 ⁇ , 3.0 ⁇ , 3.5 ⁇ , 4.0 ⁇ , 4.5 ⁇ , 5.0 ⁇ , 5.5 ⁇ , 6.0 ⁇ , 6.5 ⁇ , 7.0 ⁇ , 7.5 ⁇ , 8.0 ⁇ , 8.5 ⁇ , 9.0 ⁇ , 9.5 ⁇ , or 10.0 ⁇ or within a range defined by any two of the aforementioned amounts and wherein the platinum-based antineoplastic agent is present in an amount of 0.1 ⁇ to 10 ⁇ , such as 0.1 ⁇ , 0.5 ⁇ , 1.0 ⁇ , 1.5 ⁇ , 2 .0 ⁇ , 2.5 ⁇ , 3.0 ⁇ , 3.5 ⁇ , 4.0 ⁇ , 4.5 ⁇ , 5.0 ⁇ , 5.5 ⁇ , 6.0 ⁇ , 6.5 ⁇ , 7.0 ⁇ , 7.5
  • said product combination inhibits the growth of bladder cancer.
  • the compound of Formula (I) is formulated for oral or parenteral administration.
  • the platinum-based antineoplastic agent is formulated for oral or parenteral administration.
  • the compound of Formula (I) and the platinum-based antineoplastic agent are provided to a subject in a single formulation or a single dosage.
  • the compound of Formula (I) and the platinum- based antineoplastic agent are formulated for oral or parenteral administration.
  • the product combination reduces bladder cancer tumor size.
  • Some embodiments provided herein relate to a method of inhibiting or delaying the growth of bladder cancer in a subject.
  • the method comprises administering to a subject having bladder cancer a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
  • R 1 is methyl; R 2 is hydrogen; R 3 is -OH; R 4 is hydrogen; R 5 is hydrogen; R 6 is hydrogen.
  • the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a platinum-based antineoplastic agent.
  • the bladder cancer is inhibited or treated.
  • the bladder cancer comprises transitional cell carcinoma, squamous cell carcinoma, and/or adenocarcinomas of the bladder.
  • said method inhibits the growth of bladder cancer.
  • said method inhibits or delays the onset of bladder cancer.
  • the platinum- based antineoplastic agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, or satraplatin, or analogues or derivatives thereof.
  • the compound of Formula (I) is administered to the subject orally or parenterally.
  • the platinum-based antineoplastic agent is administered to the subject orally or parenterally.
  • the compound of Formula (I) and the platinum-based antineoplastic agent are administered to the subject orally or parenterally.
  • the bladder cancer tumor size is reduced.
  • the product combination which can be used in such methods, comprises a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
  • R 1 is methyl
  • R 2 is hydrogen
  • R 3 is -OH
  • R 4 is hydrogen
  • R 5 is hydrogen
  • R 6 is hydrogen
  • the product combination and methods of use thereof further comprises a therapeutically effective amount of a hormone deprivation agent.
  • the hormone deprivation agent is an anti-testosterone or androgen deprivation agent or an anti-estrogen or estrogen deprivation agent.
  • the androgen deprivation agent is orteronel, cyproterone acetate, flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, galeterone, abiraterone, finasteride, ethyl stilbestrol (DES), megestrol acetate, fosfestrol, estramustine phosphate, leuprolide, triptorelin, goserelin, histrelin, buserelin, abarelix, degarelix, or derivatives, salts, or analogues thereof, or combinations thereof.
  • DES ethyl stilbestrol
  • the anti-estrogen agent is tamoxifen, clomifene, ormeloxifene, toremifene, lasofoxifene, ospemifene, raloxifene, fulvestrant, brilanestrant, elacestrant, anastrozole, letrozole, testolactone, exemestane, or derivatives, salts, or analogues thereof, or combinations thereof.
  • the estrogen deprivation agent is tamoxifen, clomifene, ormeloxifene, toremifene, lasofoxifene, ospemifene, raloxifene, fulvestrant, brilanestrant, elacestrant, anastrozole, letrozole, testolactone, exemestane, or derivatives, salts, or analogues thereof, or combinations thereof.
  • the compound of Formula (I) is present in an amount of 0.1 ⁇ to 10 ⁇ , such as 0.1 ⁇ , 0.5 ⁇ , 1.0 ⁇ , 1.5 ⁇ , 2 .0 ⁇ , 2.5 ⁇ , 3.0 ⁇ , 3.5 ⁇ , 4.0 ⁇ , 4.5 ⁇ , 5.0 ⁇ , 5.5 ⁇ , 6.0 ⁇ , 6.5 ⁇ , 7.0 ⁇ , 7.5 ⁇ , 8.0 ⁇ , 8.5 ⁇ , 9.0 ⁇ , 9.5 ⁇ , or 10.0 ⁇ or within a range defined by any two of the aforementioned amounts, and wherein the hormone deprivation agent is present in an amount of 0.1 ⁇ ⁇ 10 ⁇ , such as 0.1 ⁇ , 0.5 ⁇ , 1.0 ⁇ , 1.5 ⁇ , 2 .0 ⁇ , 2.5 ⁇ , 3.0 ⁇ , 3.5 ⁇ , 4.0 ⁇ , 4.5 ⁇ , 5.0 ⁇ , 5.5 ⁇ , 6.0 ⁇ , 6.5 ⁇ , 7.0 ⁇ , 7.5
  • the product combination and accompanying methods inhibit the growth and/or progression of bladder cancer.
  • the compound of Formula (I) is formulated for oral or parenteral administration.
  • the hormone deprivation agent is formulated for oral or parenteral administration.
  • the compound of Formula (I) and the hormone deprivation agent are provided to a subject in a single formulation or a single dosage.
  • the compound of Formula (I) and the hormone deprivation agent are formulated for separate administration.
  • the product combination and accompanying method reduces bladder cancer tumor size.
  • Some embodiments provided herein relate to a method of inhibiting or delaying the growth of bladder cancer in a subject.
  • the method includes administering to a subject having bladder cancer, such as a subject identified or selected as one having bladder cancer, a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
  • R 1 is methyl
  • R 2 is hydrogen
  • R 3 is -OH
  • R 4 is hydrogen
  • R 5 is hydrogen
  • R 6 is hydrogen
  • the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a hormone deprivation agent, such as an androgen deprivation or estrogen deprivation agent.
  • the bladder cancer is inhibited or treated.
  • the bladder cancer comprises transitional cell carcinoma, squamous cell carcinoma, and/or adenocarcinomas of the bladder.
  • the method inhibits the growth of bladder cancer.
  • the method inhibits or delays the onset or progression of bladder cancer.
  • the hormone deprivation agent is an androgen deprivation agent or an anti-testosterone agent or an estrogen deprivation agent or an anti-estrogen agent.
  • the androgen deprivation agent is orteronel, cyproterone acetate, flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, galeterone, abiraterone, finasteride, ethylstilbestrol (DES), megestrol acetate, fosfestrol, estramustine phosphate, leuprolide, triptorelin, goserelin, histrelin, buserelin, abarelix, degarelix, or derivatives, salts, or analogues thereof, or combinations thereof.
  • DES ethylstilbestrol
  • the anti-estrogen agent is tamoxifen, clomifene, ormeloxifene, toremifene, lasofoxifene, ospemifene, raloxifene, fulvestrant, brilanestrant, elacestrant, anastrozole, letrozole, testolactone, exemestane, or derivatives, salts, or analogues thereof, or combinations thereof.
  • the compound of Formula (I) is administered to the subject orally or parenterally.
  • the hormone deprivation agent is administered to the subject orally or parenterally.
  • the compound of Formula (I) and the hormone deprivation agent are administered to the subject orally or parenterally, which can be in separate administrations.
  • bladder cancer tumor size is reduced.
  • R 1 is methyl
  • R 2 is hydrogen
  • R 3 is -OH
  • R 4 is hydrogen
  • R 5 is hydrogen
  • R 6 is hydrogen
  • the product combination further includes a therapeutically effective amount of a chemotherapy agent, optionally, wherein the chemotherapy agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
  • the chemotherapy agent is 5-fluorouracil, doxorubicin, gemcitabine, methotrexate, mitomycin C, valrubicin, or vinblastine, or analogues, derivatives, or combinations thereof.
  • the chemotherapy agent is an antineoplastic agent or a taxane-based chemotherapy agent.
  • the antineoplastic agent in a platinum-based antineoplastic agent selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, and satraplatin, or analogues or derivatives thereof.
  • the taxane-based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof.
  • the compound of Formula (I) is present in an amount of 0.1 ⁇ to 10 ⁇ , such as 0.1 ⁇ , 0.5 ⁇ , 1.0 ⁇ , 1.5 ⁇ , 2 .0 ⁇ , 2.5 ⁇ , 3.0 ⁇ , 3.5 ⁇ , 4.0 ⁇ , 4.5 ⁇ , 5.0 ⁇ , 5.5 ⁇ , 6.0 ⁇ , 6.5 ⁇ , 7.0 ⁇ , 7.5 ⁇ , 8.0 ⁇ , 8.5 ⁇ , 9.0 ⁇ , 9.5 ⁇ , or 10.0 ⁇ or within a range defined by any two of the aforementioned amounts and wherein the chemotherapy agent is present in an amount of 0.1 ⁇ to 10 ⁇ , such as 0.1 ⁇ , 0.5 ⁇ , 1.0 ⁇ , 1.5 ⁇ , 2 .0 ⁇ , 2.5 ⁇ , 3.0 ⁇ , 3.5 ⁇ , 4.0 ⁇ , 4.5 ⁇ , 5.0 ⁇ , 5.5 ⁇ , 6.0 ⁇ , 6.5 ⁇ , 7.0 ⁇ , 7.5 ⁇ , 8.0
  • the cancer is prostate cancer or bladder cancer.
  • the product combination inhibits the growth of bladder cancer or inhibits the growth of prostate cancer.
  • the compound of Formula (I) is formulated for oral or parenteral administration.
  • the chemotherapy agent is formulated for oral or parenteral administration.
  • the compound of Formula (I) and the chemotherapy agent are provided to a subject in a single formulation or a single dosage.
  • the compound of Formula (I) and the chemotherapy agent are formulated for oral or parenteral administration.
  • the product combination reduces bladder cancer tumor size or reduces prostate cancer tumor size.
  • Some embodiments provided herein relate to a method of inhibiting or delaying the growth of cancer in a subject.
  • the method includes administering to a subject having cancer a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
  • R 1 is methyl
  • R 2 is hydrogen
  • R 3 is -OH
  • R 4 is hydrogen
  • R 5 is hydrogen
  • R 6 is hydrogen
  • the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a chemotherapy agent, optionally, wherein the chemotherapy agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy; and wherein the cancer is inhibited or treated.
  • the chemotherapy agent is 5-fluorouracil, doxorubicin, gemcitabine, methotrexate, mitomycin C, valrubicin, or vinblastine, or analogues, derivatives, or combinations thereof.
  • the chemotherapy agent is an antineoplastic agent or a taxane-based chemotherapy agent.
  • the antineoplastic agent in a platinum-based antineoplastic agent selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, and satraplatin, or analogues or derivatives thereof.
  • the taxane-based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof.
  • the cancer is bladder cancer or prostate cancer.
  • the bladder cancer comprises transitional cell carcinoma, squamous cell carcinoma, and/or adenocarcinomas of the bladder.
  • the method inhibits the growth of bladder cancer or inhibits the growth or prostate cancer.
  • the method inhibits or delays the onset of bladder cancer or inhibits or delays the onset of prostate cancer.
  • the compound of Formula (I) is administered to the subject orally or parenterally.
  • the chemotherapy agent is administered to the subject orally or parenterally.
  • the compound of Formula (I) and the chemotherapy agent are administered to the subject orally or parenterally.
  • a size of a bladder cancer tumor or a size of a prostate cancer tumor is reduced.
  • Figure 1 illustrates the effect of a compound of Formula (I) on androgen receptor (AR) protein levels.
  • Cells were lysed and AR protein levels were analyzed by Western blot. Membranes were stripped and re-probed for actin following standard procedures. Results show that compound of Formula (I) decreases AR protein in human and mouse cancer cells.
  • Figure 2 illustrates Western blot results of androgen receptor protein levels.
  • TRAMP-C2 mouse prostate cancer cells (left panel) were grown in phenol red-free medium and treated with or without DHT (10 "8 M) for 24 hours. Cells were then treated with or without a compound of Formula (I) (8 ⁇ ) for 6 hours. Cells were lysed and AR protein levels were analyzed by western blot. Membranes were reprobed with anti-actin antibodies.
  • PTEN-P2 mouse prostate cancer cells (right panel) were grown in phenol red-free medium in the presence of DHT (10 "8 M) for 24 hours. Cells were treated with a compound of Formula (I) (8 ⁇ ) for 0, 2, or 6 hours or with DMSO for hours (Ctl). Cells were lysed and AR protein levels were analyzed by western blot. Membranes were stripped and reprobed with anti-actin antibodies.
  • Figures 3A-3C illustrate the toxicity of a compound of Formula (I) in prostate cancer cell lines, including LNCaP cells (Figure 3A), DU145 cells ( Figure 3B), and PC3 cells ( Figure 3C).
  • Figures 4A-4C illustrate the toxicity of a compound of Formula (I) in mouse prostate cancer cells, including in PTEN-P2 cells ( Figure 4 A) and PTEN-CAP2 cells (Figure 4B).
  • Figure 4C directly compared the effect of the compound of Formula (I) in the two cell lines, and depicts a similarity in the dose response.
  • Figures 5A-5D illustrate the toxicity of docetaxel in various cell lines, including DU145 cells (Figure 5A), PC3 cells (Figure 5B), PTEN-P2 cells (Figure 5C), and PTEN-CAP2 cells ( Figure 5D).
  • Figures 6A and 6B illustrate cell viability of PC3 cells (Figure 6A) and PTEN-P2 cells ( Figure 6B) in the presence of docetaxel alone or in combination with a compound of Formula (I).
  • Figures 7A-7C illustrate the cytotoxicity of a compound of Formula (I) in bladder cancer cell lines, including mouse MB49 cells (Figure 7A), human CRL1749 cells (Figure 7B), and human HTB5 cells ( Figure 7C).
  • Figures 8A-8C illustrate the cytotoxicity of valrubicin in mouse MB49 bladder cancer cells ( Figure 8A), of cisplatin in mouse MB49 bladder cancer cells ( Figure 8B), and of cisplatin in human CRL1749 bladder cancer cells ( Figure 8C).
  • Figure 9 illustrates treatment of cancer cells using cisplatin, a compound of Formula (I), or a combination of cisplatin and a compound of Formula (I) in human CRL1749 bladder cancer cells.
  • Figure 10 illustrates cell viability of mouse MB49 bladder cancer cells in the presence of valrubicin alone or in combination with a compound of Formula (I).
  • Embodiments provided herein relate to methods and compositions to treat, ameliorate, inhibit, prevent, or delay cancer cell growth or cancer in a subject, such as bladder cancer or prostate cancer.
  • the methods of inhibiting or delaying the growth of cancer, including bladder cancer or prostate cancer comprise administering to a subject or patient having a cancer such as a bladder cancer or a prostate cancer (e.g., a subject identified or selected as being one in need of an agent that treats or inhibits a cancer, such as prostate cancer or bladder cancer), a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I), alone or in combination with an androgen deprivation agent or therapy, an anti-estrogen agent or therapy, a biological agent or therapy, a virus-based agent or therapy, surgery, a chemotherapeutic agent or chemotherapy, such as a taxane-based chemotherapy agent, an antineoplastic agent, such as a platinum-based antineoplastic agent, radiation or radiation therapy, a statin or a
  • compositions that comprise a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I) in combination with an androgen deprivation agent, an anti-estrogen agent, a biological agent, a virus-based agent, a chemotherapeutic agent, such as a taxane-based chemotherapy agent, an antineoplastic agent, such as a platinum-based antineoplastic agent, a statin, a repurposed drug, a small molecule inhibitor, a therapeutic antibody, a CAR T cell, an immunotherapeutic agent, or any combination thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy.
  • an androgen deprivation agent such as a taxane-based chemotherapy agent
  • an antineoplastic agent such as a platinum-based antineoplastic agent, a
  • any "R" group(s) such as, without limitation, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 represent substituents that can be attached to the indicated atom.
  • An R group may be substituted or unsubstituted.
  • C a to Cb in which "a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group.
  • the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the cycloalkynyl, ring of the aryl, ring of the heteroaryl or ring of the heteroalicyclyl can contain from “a” to "b", inclusive, carbon atoms.
  • a "Ci to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH 3 ) 2 CH-, CH3CH2CH2CH2-, CH 3 CH 2 CH(CH 3 )- and/or (CH 3 ) 3 C-. If no "a” and "b" are designated with regard to an alkyl or alkenyl group, the broadest range described in these definitions is to be assumed.
  • alkyl refers to a straight or branched hydrocarbon chain that includes a fully saturated (no double or triple bonds) hydrocarbon group.
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; for example, “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and/or including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
  • the alkyl group of the compounds may be designated as "C1-C4 alkyl” or similar designations.
  • “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, e.g., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and/or hexyl.
  • the alkyl group may be substituted or unsubstituted.
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
  • An alkenyl group may be unsubstituted or substituted.
  • halogen means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and/or iodine.
  • the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O
  • naphthoquinone analog refers to a compound of Formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as defined herein.
  • salt refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the salt is an acid addition salt of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and/or phosphoric acid.
  • compositions can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid.
  • organic acid such as aliphatic or aromatic carboxylic or sulfonic acids
  • Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and/or salts with amino acids such as arginine and/or lysine.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohe
  • each center may independently be of R-configuration or S-configuration or a mixture thereof.
  • the compounds provided herein may be diastereometrically pure, diastereometrically enriched, or may be stereoisomeric mixtures.
  • each double bond may independently be E or Z a mixture thereof.
  • all tautomeric forms are also intended to be included.
  • composition refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and/or salicylic acid.
  • Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
  • physiologically acceptable defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound.
  • a "pharmaceutically acceptable carrier” refers to a substance, not itself a therapeutic agent, which may facilitate the incorporation of a compound into cells or tissues.
  • the carrier may be a liquid for the dissolution of a compound to be administered by ingestion.
  • the carrier may be a vehicle for delivery of a therapeutic agent to a subject.
  • the carrier may improve the stability, handling, or storage properties of a therapeutic agent.
  • the carrier may facilitate formation of a dose unit of a composition into a discrete article such as a capsule, tablet, film coated tablet, caplet, gel cap, pill pellet, or bead, and the like suitable for oral administration to a subject.
  • a "diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable.
  • a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
  • a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that is physiologically compatible with human cells and tissues.
  • an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, or disintegrating ability etc., to the composition.
  • a “diluent” is a type of excipient.
  • a "subject” refers to an animal that is the object of treatment, inhibition, or amelioration, observation or experiment.
  • Animal includes cold- and warm-blooded vertebrates and/or invertebrates such as fish, shellfish, or reptiles and, in particular, mammals.
  • “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and/or apes, and, in particular, humans. In some embodiments, the subject is human.
  • a patient is selected who is in need of treatment of cancer, such as a bladder cancer or a prostate cancer.
  • a patient is selected who has previously been treated for cancer, such as bladder cancer or prostate cancer.
  • a patient is selected who has previously been treated for being at risk of cancer, such as bladder cancer or prostate cancer.
  • a patient is selected who has developed a recurrence of cancer, such as bladder cancer or prostate cancer.
  • a patient is selected who has developed resistance to therapies for cancer, such as bladder cancer or prostate cancer.
  • a patient is selected who may have any combination of the aforementioned selection criteria.
  • treating do not necessarily mean total cure or abolition of the disease or condition.
  • the term “inhibit” refers to the reduction or prevention of the growth of a cancer, such as bladder cancer or prostate cancer.
  • the reduction can be by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or an amount that is within a range defined by any two of the aforementioned values.
  • the term “delay” refers to a slowing, postponement, or deferment of an event, such as the growth of a cancer, such as bladder cancer or prostate cancer, to a time which is later than would otherwise be expected.
  • the delay can be a delay of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%), or an amount within a range defined by any two of the aforementioned values.
  • the terms inhibit and delay are not to be construed as necessarily indicating a 100% inhibition or delay. A partial inhibition or delay may be realized.
  • a therapeutically effective amount is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated.
  • a therapeutically effective amount of compound can be the amount needed to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being administered the therapy. This response may occur in a tissue, system, animal, or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein.
  • the therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
  • the term "derivative” refers to a chemically modified compound wherein the modification is considered routine by the ordinary skilled chemist, such as an ester or an amide of an acid, or protecting groups such as a benzyl group for an alcohol or thiol, or a tert-butoxycarbonyl group for an amine.
  • analogue refers to a compound, which includes a chemically modified form of a specific compound or class thereof and which maintains the pharmaceutical and/or pharmacological activities characteristic of said compound or class.
  • biosimilar of an approved reference product/biological drug, such as a protein therapeutic, antibody, etc. refers to a biologic product that is similar to the reference product based upon data derived from (a) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (b) animal studies (including the assessment of toxicity); and/or (c) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product.
  • the biosimilar biological product and reference product utilize the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product.
  • the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product.
  • the route of administration, the dosage form, and/or the strength of the biological product are the same as those of the reference product.
  • the facility in which the biological product is manufactured, processed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure, and potent.
  • compositions herein are prepared or administered in a product combination e.g., with a compound of Formula (I) in combination with another therapeutic agent or therapy.
  • Additional therapeutic agents and/or therapies that can be provided with a compound of Formula (I) include for example, an androgen deprivation agent or therapy, an anti-estrogen agent or therapy, a biological agent or therapy, a virus-based agent or therapy, surgery, a chemotherapeutic agent or chemotherapy, such as a taxane-based chemotherapy agent, an antineoplastic agent, such as a platinum-based antineoplastic agent, radiation or radiation therapy, a statin or a statin therapy, a repurposed drug or a repurposed drug therapy, a small molecule inhibitor or a small molecule inhibitor therapy, a therapeutic antibody or a therapeutic antibody therapy, a CAR T cell or a CAR T cell therapy, an immunotherapeutic agent or an immunotherapy, or any combination thereof, optionally, wherein the chemotherapeutic agent
  • compositions described herein are prepared or administered in a product combination, for example, with a compound of Formula (I) in combination with a hormone deprivation therapy.
  • a hormone deprivation therapy may include, for example, an androgen deprivation therapy or an anti-estrogen agent or therapy.
  • a hormone deprivation therapy may include a therapy, such as a surgical procedure, or administration of an agent.
  • ADT androgen deprivation therapy
  • Surgical methods of ADT include surgical orchiectomy.
  • compositions of ADT include administration of an agent, including orteronel, cyproterone acetate, flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, galeterone, abiraterone, finasteride, ethylstilbestrol (DES), megestrol acetate, fosfestrol, estramustine phosphate, leuprolide, triptorelin, goserelin, histrelin, buserelin, abarelix, degarelix, or derivatives, salts, or analogues thereof, or combinations thereof.
  • an agent including orteronel, cyproterone acetate, flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, galeterone, abiraterone, finasteride, ethylstilbestrol (DES), megestrol acetate, fosfestrol, estramus
  • anti-estrogen therapy or estrogen deprivation agent (anti-ER therapy) refers to a treatment or amelioration of a disease or condition in which the level of estrogen hormones in a patient are reduced, typically by surgical or pharmaceutical methods.
  • Surgical methods of anti-ER therapy include surgical ovariectomy.
  • compositions of anti-ER include administration of tamoxifen, clomifene, ormeloxifene, toremifene, lasofoxifene, ospemifene, raloxifene, fulvestrant, brilanestrant, elacestrant, anastrozole, letrozole, testolactone, exemestane, or derivatives, salts, or analogues thereof, or combinations thereof.
  • biological agent refers to any chemical or biochemical compound produced by a living organism, which can include a prokaryotic cell line, a eukaryotic cell line, a mammalian cell line, a microbial cell line, an insect cell line, a plant cell line, a mixed cell line, a naturally occurring cell line, or a synthetically engineered cell line.
  • a biologic can include large macromolecules such as proteins, polysaccharides, lipids, and/or nucleic acids, as well as small molecules such as primary metabolites, secondary metabolites, and/or natural products.
  • a biologic includes Bacillus Calmette-Guerin (BCG) vaccine, sargramostim, filgrastim, pegfilgrastim, recombinant interleukin-12, or interferon alpha, or a combination thereof.
  • BCG Bacillus Calmette-Guerin
  • virus-based therapy refers to the use of virus or virus like particles for use in the treatment, inhibition, or amelioration of a disease or condition.
  • a virus-based therapy includes use of a reovirus, bunyavirus, flavivirus, rubivirus, filovirus, arenavirus, arterivirus, or calicivirus.
  • a virus-based therapy includes a retrovirus, an adenoviral vector, (including the oncolytic adenovirus vector CG0070 (Cold Genesys)), or a Coxsackievirus A21 (CVA21; CAVATAK, Viralytics), or a combination thereof.
  • chemotherapy refers to any therapy that includes natural or synthetic chemotherapeutic agents now known or to be developed in the medical arts.
  • chemotherapeutic agents include the numerous cancer drugs that are currently available.
  • chemotherapy also includes any drug, natural or synthetic, that is intended to treat, inhibit, or ameliorate a disease state, such as cancer e.g., bladder cancer or prostate cancer.
  • chemotherapy may include the administration of several state of the art drugs intended to treat, inhibit, or ameliorate the disease state, such as cancer e.g., bladder cancer or prostate cancer.
  • a chemotherapy comprises gemcitabine, cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, mustine, vincristine, procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, etoposide, epirubicin, capecitabine, methotrexate, folinic acid, lenalidomide, pemetrexed, azacitidine and analog decitabine, mitomycin C, apaziquone, eribulin, valrubicin, vinflunine, pirarubicine, pralatrexate, temsirolimus, sirolimus, ifosfamide, irinotecan, rubitecan, or AZD4877, or any combination thereof.
  • the chemotherapy is a taxane-based chemotherapy. In some embodiments, the chemotherapy is a platinum-based antineoplastic chemotherapy. In some embodiments, the chemotherapeutic agent or chemotherapy is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy.
  • Taxanes are a class of diterpenoid drugs that have anti-tumor activity against a wide range of human cancers.
  • Paclitaxel was originally isolated from the bark of the Yew tree, and was known to act by interfering with the normal function of microtubule breakdown. Paclitaxel binds to the ⁇ subunit of tubulin, the building blocks of microtubules, causing hyper-stabilization of the microtubule structures. The resulting paclitaxel/microtubule structure is unable to disassemble, thereby arresting mitosis and inhibiting angiogenesis.
  • a taxane-based chemotherapy comprises docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or combinations, analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof.
  • An antineoplastic agent is an agent that inhibits or prevents the growth and/or spread of tumors or malignant cells, and may include, for example, nucleoside analogues, antifolates, antimetabolites, enzyme inhibitors such as topoisomerase I inhibitors, anthracyclines, podophyllotoxins, alkaloids, alkylating agents, platinum compounds, antibodies, tyrosine kinase inhibitors, mTOR inhibitors, retinoids, immunomodulatory agents, histone deacetylase inhibitors.
  • an antineoplastic agent may include, for example, afatinib, aflibercept, alemtuzumab, alitretinoin, altretamine, anagrelide, arsenic trioxide, asparaginase, axitinib, azacitidine, BCG vaccine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, capecitabine, carboplatin, carmofur, carmustine, cetuximab, chlorambucil, chlormethine, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dasatinib, daunorubicin, decitabine, denileukin difti
  • platinum-based antineoplastic agents are a class of platinum containing agents for use in cancer treatment, and are platinum based alkylating agents. Platinum-based antineoplastic agents inhibit DNA repair and/or DNA synthesis in cells, including cancer cells.
  • the platinum-based antineoplastic chemotherapy comprises cisplatin, carboplatin, dicycloplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, or satraplatin, or analogues or derivatives thereof.
  • the term "radiation therapy” refers to the medical use of ionizing radiation as part of a cancer therapy designed to kill malignant cells that are progressing through the cell cycle (e.g., in any phase of the cell cycle).
  • the radiation therapy may be internal or external radiotherapy.
  • External radiotherapy involves targeting doses (or "fractions") of high-energy beams of radiation, either X-rays or gamma rays, to the tumor.
  • Internal radiotherapy involves positioning the source of radioactivity inside the body close to the tumor. This can be achieved in two ways: by brachytherapy or by radioisotope therapy.
  • Brachytherapy involves placing a solid source of radiation next to a tumor to give a high dose of radiotherapy.
  • Radioisotope therapy involves administration of a radioactive substance, a radioisotope, either as an intravenous injection, or as an oral capsule or liquid.
  • statin refers to any of a class of lipid-lowering drugs that reduce serum cholesterol levels by inhibiting HMG-CoA reductase, a key enzyme involved in the biosynthesis of cholesterol, the mevalonate pathway or HMG-CoA reductase pathway.
  • statins can comprise atorvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and/or simvastatin, or combinations thereof, or a combination of a statin and another agent, such as ezetimibe/simvastatin.
  • repurposed drug therapy refers to a strategy by which a new or additional value is generated from a drug by targeting a disease other than those diseases for which the drug was originally intended.
  • a repurposed drug therapy comprises but is in no way limited to eflornithine, indinavir, metformin, or ritonavir, or a combination thereof.
  • small molecule inhibitor therapy refers to small organic molecules, peptides, antibodies, cyclic peptides and/or peptidomimetics that are small molecules, such as less than 10,000 Daltons (but not zero), and that act by inhibition, now known or to be developed in the medical arts.
  • a small molecule inhibitor therapy comprises belinostat, bortezomib, copanlisib, crizotinib, imatinib, dasatinib, dovitinib, rapamycin, everolimus, sirolimus, tipifarnib, pazopanib, alisertib, sapanisertib, lapatinib, lonafarnib, merestinib, olaparib, palbociclib, bosutinib, sorafenib, erlotinib, sunitinib, cabozantinib, gefitinib, ixazomib, vistusertib, vorinostat, entinostat vandetanib, BAY1163877, MLN8054, PLX3397, or BGJ398, or any combination thereof.
  • a therapeutic antibody therapy refers to any antibody, now known or to be developed in the medical arts, which can be administered to a subject as an active agent, including derivatives and fragments thereof, or antigen-specific ligand molecules, such as antibody Fab fragments, or antibody Fc fragments, synthetic receptors, or soluble receptors, which selectively bind a target antigen.
  • a therapeutic antibody therapy comprises cetuximab, ritixumab, bevacizumab, ranibizumab, trastuzumab, or panitumumab, fragments thereof, or any combination thereof, which may be presented on one or more CAR T cells.
  • an immunotherapy refers to a therapy now known or to be developed in the medical arts for a disease that relies on an immune response.
  • an immunotherapy comprises nivolumab, durvalumab, pembrolizumab, atezolizumab, ipilimumab, tremelimumab, CA-170, NEO-PV-01, or a tumor cell-derived vaccine therapy, or any combination thereof.
  • coadministration of pharmacologically active compounds refers to the delivery of two or more separate chemical entities, whether in vitro or in vivo.
  • Coadministration refers to the simultaneous delivery of separate agents; to the simultaneous delivery of a mixture of agents; as well as to the delivery of one agent followed by delivery of a second agent or additional agents. In all cases, agents that are coadministered are intended to work in conjunction with each other.
  • the term "in combination” refers to a concomitant delivery of one compound with one or more compounds.
  • the compounds may be administered in combination by simultaneous administration or administration of one compound before or after administration of another compound, such as within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 minutes or within a range defined by any two of the aforementioned time points.
  • cancer refers to a class of diseases of humans (and animals) characterized by uncontrolled cellular growth.
  • cancer is used interchangeably with the terms “tumor,” “malignancy,” “hyperproliferation” and “neoplasm(s) .”
  • cancer cell(s) is interchangeable with the terms “tumor cell(s),” “malignant cell(s),” “hyperproliferative cell(s),” and “neoplastic cell(s)” unless otherwise explicitly indicated.
  • hypoproliferative hyperproliferative
  • hyperplastic neoplastic
  • malignant neoplastic
  • neoplasm(s) are meant to include all types of hyperproliferative growth, hyperplastic growth, neoplastic growth, cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness.
  • bladder cancer refers to cellular carcinomas characterized by uncontrolled cell growth of bladder cells.
  • bladder cancer includes urothelial cell carcinoma, which is a malignancy of the specialized transitional epithelium lining the organ.
  • Urothelial cell carcinomas of the bladder are classified into two categories termed non-muscle invasive bladder cancer and muscle invasive bladder cancer.
  • Non-muscle invasive bladder cancer is highly treatable, usually by complete resection of the tumor followed by immunotherapy with intra-vesical BCG vaccine or intra- vesical chemotherapy.
  • bladder cancer examples include squamous cell carcinoma, adenocarcinoma, sarcoma, small cell carcinoma, and/or secondary deposits from cancers elsewhere in the body.
  • Bladder cancer may include transitional cell carcinoma, squamous cell carcinoma, and/or adenocarcinomas of the bladder.
  • Prostate cancer refers to cellular carcinomas characterized by uncontrolled cell growth of prostate cells.
  • Prostate cancer may include malignant mammalian cancers, including adenocarcinomas, derived from prostate epithelial cells.
  • Prostate cancers described in the current application may include both metastatic and non-metastatic cancers.
  • the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least.”
  • the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components.
  • the section below describes some of the compounds that can be used to treat cancer, or inhibit or delay the growth of cancer cells, especially bladder cancer cells alone or in combination with one or more androgen deprivation therapies (e.g., castration, hormonal castration, hormonal ablation, or hormone therapy).
  • androgen deprivation therapies e.g., castration, hormonal castration, hormonal ablation, or hormone therapy.
  • AR is expressed in bladder epithelial cells and its expression is increased in tumor cells compared to normal cells in human tissue. Lombard et al., Endocrinol, 2015, 22, R265-R277.
  • AR antagonists such as enzalutamide, flutamide and bicalutamide inhibit cell proliferation and invasion in AR-positive cells (Miyamoto et al., J Natl Cancer Inst, 2007, 99, 558-568; Kawahara et al., Urol Oncol, 2016, 34, 432.
  • Bladder cancer is categorized in various stages, including stage 0a (including non-invasive papillary carcinoma, no regional lymph node metastasis, and no distant metastasis); stage Ois (including carcinoma in situ (flat tumor), no regional lymph node metastasis, and no distant metastasis); stage I (including tumor invasion of subepithelial connective tissue, no regional lymph node metastasis, and no distant metastasis); stage II (including tumor invasion of superficial muscle (inner half) or tumor invasion of deep muscle (outer half), no regional lymph node metastasis, and no distant metastasis); stage III (including tumor invasion of perivesical tissue on a microscopic or macroscopic level, tumor invasion of prostate, uterus, or vagina, no regional lymph node metastasis, and no distant metastasis); stage IV (including any of stages 0a, Ois, I, II, or III, tumor invasion of pelvic wall or abdominal wall, metastasis in a single lymph node from less than 2
  • the AR axis is a therapeutic target for bladder cancer.
  • a compound of Formula (I) acts as an antagonist to AR by decreasing AR expression.
  • compositions including a compound of Formula (I) also have anti-proliferation activity in bladder cancer.
  • Figure 1 depicts a dose-dependent decrease in AR in prostate cancer cell lines is observed when contacting mouse prostate cancer cells (PTEN-P2 cells) and human cancer cells (LNCaP cells) grown in the presence of 10 "8 M DHT, and the incubated with increasing concentrations of a compound of Formula
  • Metastatic bladder cancers are sometimes treated with platinum-based agents. Despite initial sensitivity to cisplatin-based chemotherapy regimens, long term control rates of advanced or metastatic disease remain less than 5%. There is currently no standard second-line chemotherapy for metastatic urothelial cancer previously treated with a platinum-based regimen. In this setting, paclitaxel and docetaxel are commonly used despite overall response rates of less than 20%.
  • Recurrence rate of bladder cancer also presents an additional challenge for bladder cancer treatment.
  • BCG Bacillus Calmette-Guerin
  • BCG treatment leads to up to 80% failure rates.
  • Response rates to current second line intravesical therapies average less than 20%.
  • the methods and compositions are useful for the treatment or inhibition of bladder cancer that has developed resistance to therapies, for example, androgen deprivation therapies, antineoplastic agents, chemotherapies, radiation therapies, surgical therapies, or other therapies, optionally, wherein the chemotherapy or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
  • therapies for example, androgen deprivation therapies, antineoplastic agents, chemotherapies, radiation therapies, surgical therapies, or other therapies, optionally, wherein the chemotherapy or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
  • the methods and compositions provided herein provide surprising and unexpected improvements in the treatment or inhibition of bladder cancer, including in subjects that have developed resistance to therapies of bladder cancer.
  • the targeting of AR during chemotherapy is a surprising and unexpected strategy to overcome or delay the acquisition of GC resistance in patients with AR-positive bladder cancer.
  • AR expression was up-regulated in cells rendered resistant to cisplatin in vitro, while analysis of human clinical specimen showed a correlation between AR levels and cisplatin resistance (Kashiwagi et al., Oncotarget, 2016, 7, 49169-49179).
  • upregulation of AR expression was observed in gemcitabine-resistant cells compared to non- resistant cells and treatment with AR antagonist enzalutamide inhibited the proliferation of the resistant cell lines (Kameyama et al. Int J Oncol, 2017, 50, 75-84).
  • the section below provides more details on the use of compounds of Formula (I) to inhibit or delay the growth of cancer cells, in particular, bladder cancer cells.
  • prostate tumor growth is androgen dependent. Androgens are used by prostate cancer cells for both proliferation as well as regulation, and are vital for maintaining the growth and survival of the cancer cell.
  • the main androgen that circulates is testosterone, which is mainly produced in the testes.
  • Extragonadal sources of androgen synthesis do, however, exist and may play a role in the development of castration- resistant forms of prostate cancer.
  • androgen dependent prostate cancer therapy focuses on minimizing testicular synthesis of androgens with luteinizing hormone releasing hormone ("LHRH”) agonists or antagonists.
  • LHRH luteinizing hormone releasing hormone
  • Some therapies also focus on modulating the androgen receptor itself, or its downstream signaling pathway.
  • Androgen dependent prostate cancer will eventually progress into castration-resistant prostate cancer ("CRPC"). Although these patients are “androgen insensitive,” researchers have discovered that androgen-responsive genes are still expressed, implying that the androgen-receptor signaling pathway may still be an important target in CRPC patients. Schweizer et al., Therapeutic Advances in Urology, 4(4), 167-178.
  • brachytherapy which involves the implantation of a small amount of radioactive material (seeds) into the prostate.
  • This radiation therapy method is an effective treatment for early-stage prostate cancer.
  • GnRH gonadotropin-releasing hormone
  • PSA prostate-specific antigen
  • the present disclosure relates to pharmaceutical compositions containing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and methods of using these compounds alone or in combination with an additional therapy or therapeutic agent to inhibit, delay, treat, or prevent cancer cell growth or cancer, such as bladder cancer or prostate cancer, in a subject in need thereof.
  • Other embodiments disclosed herein relate to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, alone or in combination with an additional therapy or therapeutic agent, to inhibit, delay, treat, or prevent cancer cell growth or cancer, such as bladder cancer or prostate cancer, in a subject in need thereof.
  • inventions disclosed herein relate to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, alone or in combination with a therapeutic agent, in the manufacture of a medicament for inhibiting, delaying, treating, or preventing cancer cell growth or cancer, such as bladder cancer or prostate cancer, in a subject in need thereof.
  • a product combination and/or the use of a product combination containing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a therapeutic agent, as described herein, to inhibit, delay, treat, or prevent cancer cell growth or cancer, such as bladder cancer or prostate cancer, in a subject in need thereof and/or for the manufacture of a product combination for inhibiting, delaying, treating, or preventing cancer cell growth or cancer, such as bladder cancer or prostate cancer, in a subject in need thereof.
  • a product combination containing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a therapeutic agent, as described herein, to inhibit, delay, treat, or prevent cancer cell growth or cancer, such as bladder cancer or prostate cancer, in a subject in need thereof and/or for the manufacture of a product combination for inhibiting, delaying, treating, or preventing cancer cell growth or cancer, such as bladder cancer or prostate cancer, in a subject in need thereof.
  • the compound of Formula (I) has the following structure:
  • R 1 can be selected from hydrogen, halogen, an optionally substituted C1-18 alkyl, an optionally substituted C2-18 alkenyl, -OR 7 and -SR 8 ;
  • R 2 can be selected from hydrogen, halogen, an optionally substituted Ci-6 alkyl, an optionally substituted C2-6 alkenyl, -OR 9 and -SR 10 ;
  • R 3 can be selected from hydrogen, an optionally substituted Ci-6 alkyl, and -OR 11 ;
  • R 4 can be selected from hydrogen, an optionally substituted Ci-6 alkyl, and -OR 12 ;
  • R 5 can be selected from hydrogen, an optionally substituted Ci-6 alkyl, and -OR 13 ;
  • R 6 can be selected from hydrogen, an optionally substituted Ci-e alkyl, and -OR 14 ; and
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 can be independently selected from hydrogen and an optionally
  • R 1 can be hydrogen. In some embodiments, R 1 can be halogen. In some embodiments, R 1 can be chloro. In some embodiments, R 1 can be an optionally substituted C1-18 alkyl.
  • optionally substituted Ci-is-alkyls include, but are not limited to, optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decanyl, undecanyl, dodecanyl, tridecanyl, tetradecanyl, pentadecanyl, hexadecanyl, heptadecanyl, octadecanyl, and phytanyl.
  • Ci-is-alkyls can be branched or straight- chained.
  • R 1 can be an optionally substituted Ci-6 alkyl.
  • R 1 can be methyl.
  • R 1 can be t-butyl.
  • R 1 can be an optionally substituted C2-18 alkenyl.
  • optionally substituted C2-is-alkenyls include, but are not limited to, optionally substituted variants of the following: ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, and phytenyl.
  • Optionally substituted C2-is-alkenyls can be branched or straight-chained, and can include one or more double bonds.
  • R 1 can be an optionally substituted C2-6 alkenyl.
  • R 1 can be -OR 7 , wherein R 7 is hydrogen.
  • R 1 can be -OR 7 , wherein R 7 is an optionally substituted Ci-6 alkyl.
  • R 1 can be -OR 7 , wherein R 7 is methyl.
  • R 1 can be -SR 8 , wherein R 8 is hydrogen.
  • R 1 can be -SR 8 , wherein R 8 is an optionally substituted Ci-6 alkyl.
  • R 1 can be -SR 8 , wherein R 8 is Ci-6 alkyl optionally substituted with hydroxy. In some embodiments, R 1 can be -SR 8 , wherein R 8 is -CH2CH2OH. [0130] In some embodiments, R 2 can be hydrogen. In some embodiments, R 2 can be halogen. In some embodiments, R 2 can be chloro. In some embodiments, R 2 can be an optionally substituted Ci-6 alkyl.
  • Ci-6-alkyls examples include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight- chained).
  • R 2 can be methyl.
  • R 2 can be an optionally substituted C2-6 alkenyl.
  • optionally substituted C2-6-alkenyls include optionally substituted variants of the following: ethenyl, propenyl, butenyl, pentenyl (branched and straight-chained), and hexenyl (branched and straight-chained).
  • R 2 can be -OR 9 , wherein R 9 is hydrogen.
  • R 2 can be -OR 9 , wherein R 9 is an optionally substituted Ci-6 alkyl.
  • R 2 can be -OR 9 , wherein R 9 is methyl.
  • R 2 can be -SR 10 , wherein R 10 is hydrogen.
  • R 2 can be - SR 10 , wherein R 10 is an optionally substituted Ci-6 alkyl. In some embodiments, R 2 can be - SR 10 , wherein R 10 is Ci-6 alkyl optionally substituted with hydroxy. In some embodiments, R 2 can be -SR 10 , wherein R 10 is -CH2CH2OH.
  • R 3 can be hydrogen. In some embodiments, R 3 can be an optionally substituted Ci-6 alkyl. In some embodiments, R 3 can be -OR 11 , wherein R 11 is hydrogen. In some embodiments, R 3 can be -OR 11 , wherein R 11 is an optionally substituted Ci-6 alkyl.
  • R 4 can be hydrogen. In some embodiments, R 4 can be an optionally substituted Ci-6 alkyl. In some embodiments, R 4 can be t-butyl. In some embodiments, R 4 can be -OR 12 , wherein R 12 is hydrogen. In some embodiments, R 4 can be - OR 12 , wherein R 12 is an optionally substituted Ci-6 alkyl.
  • R 5 can be hydrogen. In some embodiments, R 5 can be an optionally substituted Ci-6 alkyl. In some embodiments, R 5 can be -OR 13 , wherein R 13 is hydrogen. In some embodiments, R 5 can be -OR 13 , wherein R 13 is an optionally substituted Ci-6 alkyl.
  • R 6 can be hydrogen. In some embodiments, R 6 can be an optionally substituted Ci-6 alkyl. In some embodiments, R 6 can be -OR 14 , wherein R 14 is hydrogen. In some embodiments, R 6 can be -OR 14 , wherein R 13 is an optionally substituted Ci-6 alkyl.
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 can be independently selected from hydrogen. In some embodiments, R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 can be independently selected from Ci-6 alkyl. In some embodiments, R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 can be independently selected from Ci-6 alkyl, wherein the Ci-6 alkyl can be optionally substituted with a group selected from halogen, hydroxy, and Ci-4 alkyl.
  • R 1 can be selected from hydrogen, halogen, an optionally substituted Ci-6 alkyl, -OR 7 and -SR 8 ;
  • R 2 can be selected from hydrogen, halogen, an optionally substituted Ci-6 alkyl, -OR 9 and -SR 10 ;
  • R 3 can be selected from hydrogen and - OR 11 ;
  • R 4 can be selected from hydrogen and an optionally substituted Ci-6 alkyl;
  • R 5 can be hydrogen;
  • R 6 can be selected from hydrogen and -OR 14 ; and
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 can be independently selected from hydrogen and an optionally substituted Ci-6 alkyl.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 can each be hydrogen.
  • R 1 can be methyl; R 3 can be -OH; and R 2 , R 4 , R 5 and R 6 can each be hydrogen.
  • R 3 and R 6 can each be -OH; and R 1 , R 2 , R 4 and R 5 can each be hydrogen.
  • R 3 can be -OH; and R 1 , R 2 , R 4 , R 5 and R 6 can each be hydrogen.
  • R 1 and R 2 can each be -SCH2CH2OH; and R 3 , R 4 , R 5 and R 6 can each be hydrogen.
  • R 1 and R 2 can each be -OCH3; and R 3 , R 4 , R 5 and R 6 can each be hydrogen. In some embodiments, R 1 can be -OCH3; and R 2 , R 3 , R 4 , R 5 and R 6 can each be hydrogen. In some embodiments, R 1 can be methyl; and R 2 , R 3 , R 4 , R 5 and R 6 can each be hydrogen. In some embodiments, R 1 and R 2 can each be chloro; and R 3 , R 4 , R 5 and R 6 can each be hydrogen. In some embodiments, R 1 can be -OH; and R 2 , R 3 , R 4 , R 5 and R 6 can each be hydrogen.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 cannot be hydrogen.
  • R 1 when R 1 is methyl; and R 2 , R 4 , R 5 and R 6 are each hydrogen; then R 3 cannot be -OH.
  • R 1 , R 2 , R 4 and R 5 are each hydrogen; then at least one of R 3 and R 6 cannot be -OH.
  • R 1 , R 2 , R 4 , R 5 and R 6 are each hydrogen; then R 3 cannot be -OH.
  • R 3 , R 4 , R 5 and R 6 are each hydrogen; then at least one of R 1 and R 2 cannot be -SCH2CH2OH. In some embodiments, when R 3 , R 4 , R 5 and R 6 are each hydrogen; then at least one of R 1 and R 2 cannot be -OCH3. In some embodiments, when R 2 , R 3 , R 4 , R 5 and R 6 are each hydrogen; then R 1 cannot be -OCH3. In some embodiments, when R 2 , R 3 , R 4 , R 5 and R 6 are each hydrogen; then R 1 cannot be methyl.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is prepared with a pharmaceutically acceptable carrier that facilitates the incorporation of a compound into cells or tissues.
  • the pharmaceutical composition including a compound of Formula (I) may include a compound of Formula (I), at least one pharmaceutically acceptable carrier, at least one excipient, and chemotherapeutic agent, or antineoplastic agent, optionally, wherein the chemotherapeutic agent or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
  • the at least one excipient may be a binder, a disintegrant, a surfactant, or a stabilizer.
  • Cancer therapies including existing therapies for cancer, such as bladder cancer or prostate cancer, may include a therapy comprising an androgen deprivation agent or therapy, an anti-estrogen agent or therapy, a biological agent or therapy, a virus-based agent or therapy, surgery, a chemotherapeutic agent or chemotherapy, such as a taxane-based chemotherapeutic agent, an antineoplastic agent, such as a platinum-based antineoplastic agent, radiation or radiation therapy, a statin or a statin therapy, a repurposed drug or a repurposed drug therapy, a small molecule inhibitor or a small molecule inhibitor therapy, a therapeutic antibody or a therapeutic antibody therapy, a CAR T cell or a CAR T cell therapy, an immunotherapeutic agent or an immunotherapy, or any combination thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an and
  • a subject suffering from cancer such as bladder cancer or prostate cancer is provided one or more of the aforementioned therapies before, after, or simultaneous with administration of a compound of Formula (I).
  • a cancer therapy contemplated herein can also comprise a standard of care cancer therapy treatment.
  • some embodiments included herein may comprise a standard of care cancer therapy treatment in combination with a compound of Formula (I) with or without additional administration of an androgen deprivation agent or therapy, an anti-estrogen agent or therapy, a biological agent or therapy, a virus-based agent or therapy, surgery, a chemotherapeutic agent or chemotherapy, such as a taxane-based chemotherapeutic agent, an antineoplastic agent, such as a platinum-based antineoplastic agent, radiation or radiation therapy, a statin or a statin therapy, a repurposed drug or a repurposed drug therapy, a small molecule inhibitor or a small molecule inhibitor therapy, a therapeutic antibody or a therapeutic antibody therapy, a CAR T cell or a CAR T cell therapy, an immunotherapeutic agent or an immunotherapy, or any combination thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone depriv
  • compositions described herein are prepared or administered in a product combination, for example, with a compound of Formula (I) in combination with a hormone deprivation therapy.
  • a hormone deprivation therapy may include, for example, an androgen deprivation therapy or an anti-estrogen agent or therapy.
  • a hormone deprivation therapy may include a therapy, such as a surgical procedure, or administration of an agent.
  • Androgen deprivation therapies include a therapy for a disease or condition in which the level of androgen hormones in a patient are reduced, typically by surgical or pharmaceutical methods.
  • Surgical methods of ADT can comprise surgical orchiectomy, which refers to removal of the testes.
  • Pharmaceutical ADT therapies may comprise:
  • Orteronel includes TAK-700.
  • Orteronel includes 6-(7-Hydroxy-6,7-dihydro-5H-pyrrolo[l,2- c]imidazol-7-yl)-N-methyl-naphthalene-2-carboxamide);
  • Cyproterone acetate (including pharmaceutically acceptable salts thereof, including Androcur and CYPROSTAT®.
  • Cyproterone acetate can include lR,3aS,3bR,7aR,8aS,8bS,8cS,10aS)-l-acetyl-5-chloro-8b,10a-dimethyl-7-oxo- l,2,3,3a,3b,7,7a,8,8a,8b,8c,9, 10,10a-tetradecahydrocyclopenta-[a]cyclopropa- [g]phenanthren-l-yl acetate);
  • flutamide (including pharmaceutically acceptable salts thereof, including hydroxyflutamide and 2-amino-5-nitro-4-(trifluoromethyl)phenol.
  • Flutamide includes Eulexin, Flutamin, Cytomid, Flutamide USP25, Cebatrol, Niftholide, and Niftolid.
  • Flutamide includes 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide);
  • nilutamide (including pharmaceutically acceptable salts thereof.
  • Nilutamide includes Nilandron and Anandron.
  • Nilutamide includes 5,5-dimethyl-3-[4-nitro- 3-(trifluoromethyl)phenyl] imidazolidine-2,4-dione);
  • Bicalutamide (including pharmaceutically acceptable salts thereof, including BICALOX®, CASODEX®, COSUDEX®, Calutide, and Kalumid.
  • Bicalutamide includes N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2- methylpropanamide);
  • Enzalutamide includes pharmaceutically acceptable salts thereof.
  • Enzalutamide includes Xtandi (including Xtandi oral).
  • Enzalutamide includes (4-(3-(4- cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro- N-methy lb enzami de));
  • apalutamide including pharmaceutically acceptable salts thereof.
  • Apalutamide includes 4- ⁇ 7-[6-Cyano-5-(trifluoromethyl)-3-pyridinyl]-8-oxo-6-thioxo-5,7- diazaspiro[3.4]oct-5-yl ⁇ -2-fluoro-N-methylbenzamide);
  • doralutamide including pharmaceutically acceptable salts thereof.
  • Doralutamide includes N-((S)-l-(3-(3-chloro-4-cyanophenyl)-lH-pyrazol-l-yl)propan-2-yl)- 5-(l-hydroxyethyl)-lH-pyrazole-3-carboxamide);
  • Galeterone (including pharmaceutically acceptable salts thereof.
  • Galeterone includes 17-(lH-benzimidazol-l-yl)androsta-5, 16-dien-3P-ol);
  • abiraterone (including pharmaceutically acceptable salts thereof, including abiraterone acetate.
  • Abiraterone includes Abretone and ZYTIGATM.
  • Abiraterone includes (3P)-17-(pyridin-3-yl)androsta-5,16-dien-3-ol.
  • Abiraterone includes Abretone and ZYTIGA®);
  • finasteride (including pharmaceutically acceptable salts thereof.
  • Finasteride includes MK-906, Proscar and Propecia.
  • Finasteride includes N-(l,l- dimethylethyl)-3 -oxo-(5a, 17P)-4-azaandrost- 1 -ene- 17-carboxamide);
  • ethylstilbestrol including diethylstilbestrol (including pharmaceutically acceptable salts thereof, including diethylstilbestrol disodium, diethylstilbestrol diphosphate, and Diethylstilbestrol dipropionate.
  • Diethylstilboestrol includes DISTILBENE®, Stilbestrol, and Stilphostrol.
  • Diethylstilboestrol includes 4,4'-(3E)-hex-3-ene-3,4-diyldiphenol) or ethylstilbestrol (including pharmaceutically acceptable salts thereof.
  • Ethylstilboestrol includes BRN 3136095 and alpha-ethyl-4,4'-stilbenediol));
  • megestrol acetate (including pharmaceutically acceptable salts thereof.
  • Megestrol acetate includes Megace and Megace ES.
  • Megestrol acetate includes 17a- (acetyloxy)6-methylpregna-4,6-diene-3,20-dione);
  • fosfestrol (including pharmaceutically acceptable salts thereof, including fosfestrol sodium and fosfestrol tetrasodium.
  • Fosfestrol includes fosfestrol, fosfestrolo, Honvan, and Stilbostatin.
  • Fosfestrol includes [4-[4-(4-phosphonooxyphenyl)hex-3-en-3-yl] phenoxy]phosphonic acid and diethylstilbestrol diphosphate);
  • estramustine phosphate (including pharmaceutically acceptable slats thereof.
  • Estramustine phosphate includes Emcyt and Estracyt.
  • Estramustine phosphate includes [(8R,9S, 13S,14S,17S)-13-methyl-17-phosphonooxy-6,7,8,9, l 1,12, 14,15, 16,17- decahydrocyclopenta[a]phenanthren-3-yl] N,N-bis(2-chloroethyl)carbamate);
  • leuprolide (including pharmaceutically acceptable salts thereof, including leuprolide acetate.
  • Leuprolide includes leuprorelin, Lupron (including Lupron injection and Lupron depot), Viadur, Eligard, and Leupromer.
  • Leuprolide includes 5-oxo-L-prolyl-L- histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-Lprolinamide acetate);
  • triptorelin (including pharmaceutically acceptable salts thereof, including triptorelin acetate and triptorelin pamoate.
  • Triptorelin includes Trelstar, Decapeptyl, Diphereline, Gonapeptyl, and Variopeptyl.
  • Triptorelin includes 5-oxo-D-prolyl-L-histidyl-L- tryptophyl-L-seryl-L-tyrosyl-3-(lH-indol-2-yl)-L-alanylleucyl-L-arginyl-L- prolylglycinamide);
  • goserelin (including pharmaceutically acceptable salts thereof, including goserelin acetate.
  • Goserelin includes Zoladex.
  • Goserelin includes N-(21-((lH-indol-3- yl)methyl)- 1 , 1 -diamino- 12-(tert-butoxymethyl)-6-(2-(2- carbamoylhydrazinecarbonyl)cyclopentanecarbonyl)-15-(4-hydroxybenzyl)-18- (hydroxymethyl)-25-(lH-imidazol-5-yl)-9-isobutyl-8,l l, 14,17,20,23-hexaoxo- 2,7,10, 13,16, 19,22-heptaazapentacos- 1 -en-24-yl)-5-oxopyrrolidine-2-carboxamide);
  • histrelin (including pharmaceutically acceptable salts thereof, including histrelin acetate. Histrelin includes Vantas and Supprelin LA. Histrelin includes 5-oxo-L- prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-l-benzyl-D-histidyl-L-leucyl-N5- (diaminomethylene)-L-ornithyl-N-ethyl-L-prolinamide);
  • buserelin (including pharmaceutically acceptable salts thereof, including buserelin acetate.
  • Beserelin includes Bigonist, SUPRADOPIN®, SURFACT®, Profact, Etilamide, and Tiloryth.
  • Buserelin includes (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)- l-[[(2S)-l-[[(2S)-5-(diaminomethylideneamino)-l-[(2S)-2-(ethylcarbamoyl)pyrrolidin-l-yl]- l-oxopentan-2-yl]amino]-4-methyl-l-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]- l-oxopropan-2-yl]amino]-3-(4-hydroxyphen
  • abarelix including pharmaceutically acceptable salts thereof, including acetyl-D-P-naphthylalanyl-D-4-chlorophenylalanyl-D-3-pyridylalanyl-L-seryl-L-N-methyl- tyrosyl-D-asparagyl-L-leucyl-L-N(8)-isopropyl-lysyl-L-prolyl-D-alanyl-amide.
  • Abarelix can include PlenaxisTM); or [0165] degarelix (including pharmaceutically acceptable salts thereof, including degarelix acetate.
  • Degarelix includes FIRMAGON® (including FIRMAGON® injection).
  • Degarelix includes D-alaninamide, N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-D- phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-4-[[[(4S)-hexahydro-2,6-dioxo- 4pyrimidinyl]carbonyl]amino]-L-phenylalanyl-4-[(aminocarbonyl)amino]-D-phenylalanyl- L-leucyl-N6-(l-methylethyl)-L-lysyl-L-prolyl);
  • Any one or more of the aforementioned ADT compounds may be provided before, after, and/or simultaneous with administration of a compound of Formula (I) to a subject that has cancer, such as bladder cancer or prostate cancer so as to treat, inhibit, or ameliorate said cancer.
  • cancer such as bladder cancer or prostate cancer
  • Anti-estrogen therapies may include therapies for a disease or condition in which the level of estrogen hormones in a patient are reduced, typically by surgical or pharmaceutical methods.
  • Surgical methods of anti-ER therapy can comprise surgical ovariectomy (removal of the ovary or ovaries).
  • Pharmaceutical anti-ER therapies may comprise:
  • Tamoxifen includes Nolvadex, Genox, Tamifen and (Z)-2-[4-(l,2-diphenylbut-l- enyl)phenoxy]-N,N-dimethylethanamine);
  • Clomifene includes Clomid and (E,Z)-2-(4-(2-chloro-l,2-diphenylethenyl) phenoxy)-N,N-diethyl-ethanamine);
  • Ormeloxifene includes centchroman, Centron, Novex-DS, Saheli, Sevista, and l-[2-[4- [(3S,4R)-7-Methoxy-2,2-dimethyl-3-phenyl-chroman-4-yl]phenoxy]ethyl]pyrrolidine);
  • toremifene (including pharmaceutically acceptable salts thereof, including toremifene acetate.
  • Toremifene includes 2- ⁇ 4-[(lZ)-4-chloro-l,2-diphenyl-but-l-en-l- yl]phenoxy ⁇ -N,N-dimethylethanamine);
  • lasofoxifene including pharmaceutically acceptable salts thereof.
  • Lasofoxifene includes Fablyn and (5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-l-ylethoxy)phenyl]- 5,6,7,8-tetrahydronaphthalen-2-ol;
  • ospemifene including pharmaceutically acceptable salts thereof.
  • Ospemifene includes Osphena and 2-(p-((Z)-4-Chloro-l,2-diphenyl-l- butenyl)phenoxy)ethanol);
  • Raloxifene includes Evista and [6-hydroxy-2-(4-hydroxyphenyl)- benzothiophen-3-yl]- [4- [2-(l -piped dyl)ethoxy]phenyl] -methanone);
  • Fulvestrant includes Faslodex and (7 ⁇ ,17 ⁇ )-7- ⁇ 9-[(4,4,5,5,5- pentafluoropentyl)sulfinyl]nonyl ⁇ estra-l,3,5(10)-triene-3,17-diol);
  • Brilanestrant includes (2E)-3- ⁇ 4-[(lE)-2-(2-chloro-4-fluorophenyl)-l-(lH-indazol-5-yl)but- 1 -en- 1 -yljphenyl ⁇ prop-2-enoic acid);
  • Elacestrant includes (6R)-6- ⁇ 2-[Ethyl( ⁇ 4-[2-(ethylamino)ethyl]phenyl ⁇ methyl)amino]-4- methoxyphenyl ⁇ -5,6,7,8-tetrahydronaphthalen-2-ol);
  • anastrozole including pharmaceutically acceptable salts thereof.
  • Anastrozole includes Arimidex and 2,2'-[5-(lH-l,2,4-triazol-l-ylmethyl)-l,3- phenylene]bis(2-methylpropanenitrile));
  • letrozole including pharmaceutically acceptable salts thereof.
  • Letrozole includes Femara and 4,4'-((lH-l,2,4-triazol-l-yl)methylene)dibenzonitrile);
  • testolactone (including pharmaceutically acceptable salts thereof.
  • Testolactone includes Teslac and (4a,S',4bR,10aR, 10b ) S',12a ) S)-10a, 12a-Dimethyl- 3,4,4a,5,6, 10a, 10b,l l, 12,12a-decahydro-2H-naphtho[2,l-f]chromene-2,8(4bH)-dione); or
  • Exemestane includes Aromasin and 6-Methylideneandrosta-l,4-diene-3,17-dione);
  • Biologies include chemical or biochemical compounds produced by a living organism provided as a composition or as part of a therapy regimen.
  • Biologic therapies can comprise: [0185] Bacillus Calmette-Guerin (BCG) vaccine (a standard of care treatment for patients with bladder cancer.
  • BCG vaccine includes biosimilar agents or strains that are used for the treatment of bladder cancer, including non-muscle invasive bladder cancer);
  • Sargramostim includes Leukine, and biosimilars
  • Filgrastim includes Neupogen, Zarxio, and biosimilars, and the pegylated formulations thereof, including pegfilgrastim;
  • interferon alpha including analogues, derivatives, and biosimilars thereof
  • Any one or more of the aforementioned biologic treatments may be administered before, after, and/or simultaneous with administration of a compound of Formula (I) so as to treat, inhibit, or ameliorate cancer, such as bladder cancer or prostate cancer.
  • virus-based therapy refers to the use of virus or virus like particles for use in the treatment or inhibition of a disease or condition.
  • a virus-based therapy may comprise a viral carrier, comprising use of a reovirus, bunyavirus, flavivirus, rubivirus, filovirus, arenavirus, arterivirus, or calicivirus.
  • a virus-based therapy may comprise a retrovirus, an adenoviral vector, (including the oncolytic adenovirus vector CG0070 (Cold Genesys)), or a Coxsackievirus A21 (CVA21; CAVATAK, Viralytics), or any combination thereof.
  • chemotherapy refers to any therapy that comprises natural or synthetic chemotherapeutic agents now known or to be developed in the medical arts.
  • chemotherapeutic agents comprise the numerous cancer drugs that are currently available.
  • chemotherapy also comprises any drug, natural or synthetic, that is intended to treat or inhibit a disease state.
  • chemotherapy may comprise the administration of several state of the art drugs intended to treat or inhibit the disease state.
  • a chemotherapy comprises gemcitabine, cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, mustine, vincristine, procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, etoposide, epirubicin, capecitabine, methotrexate, folinic acid, lenalidomide, pemetrexed, azacitidine and analog decitabine, mitomycin C, apaziquone, eribulin, valrubicin, vinflunine, pirarubicine, pralatrexate, temsirolimus, sirolimus, ifosfamide, irinotecan, rubitecan, or AZD4877, or analogues, derivatives, and any combination thereof.
  • the chemotherapeutic agent or chemotherapy is not a hormonal therapy, is not a hormone replacement therapy, is not a
  • the chemotherapy is a taxane-based chemotherapy agent or a platinum-based antineoplastic agent.
  • Taxanes are a class of diterpenoid drugs that have anti-tumor activity against a wide range of human cancers.
  • Paclitaxel was originally isolated from the bark of the Yew tree, and was known to act by interfering with the normal function of microtubule breakdown. Paclitaxel binds to the ⁇ subunit of tubulin, the building blocks of microtubules, causing hyper-stabilization of the microtubule structures. The resulting paclitaxel/microtubule structure is unable to disassemble, thereby arresting mitosis and inhibiting angiogenesis.
  • Platinum-based antineoplastic agents are a class of platinum containing agents for use in cancer therapy. Platinum-based antineoplastic agents inhibit DNA repair and/or DNA synthesis in cells, including cancer cells.
  • a taxane-based chemotherapy agent may comprise one or more of the following agents, or other taxane-based chemotherapy agents now known or to be developed in the medical arts:
  • docetaxel (including pharmaceutically acceptable salts thereof.
  • Docetaxel may include l,7p, 10P-trihydroxy-9-oxo-5p,20-epoxytax-l l-ene-2a,4,13a-triyl 4-acetate 2- benzoate 13- ⁇ (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate ⁇ , Taxotere, or Docecad);
  • Paclitaxel ((including pharmaceutically acceptable salts thereof.
  • Paclitaxel may include (2 ⁇ ,4 ⁇ ,5 ⁇ ,7 ⁇ , 10 ⁇ , 13 ⁇ )-4, 10-Bis(acetyloxy)- 13 - ⁇ [(2R,3 S)-3 -(benzoylamino)-2- hydroxy-3-phenylpropanoyl]oxy ⁇ -l,7-dihydroxy-9-oxo-5,20-epoxytax-l l-en-2-yl benzoate, Taxol, PTX);;
  • Cabazitaxel (including pharmaceutically acceptable salts thereof.
  • Cabazitaxel may include (l S,2S,3R,4S,7R,9S, 10S, 12R, 15S)-4-(Acetyloxy)-15- ⁇ [(2R,3S)-3- ⁇ [(tert-butoxy)carbonyl]amino ⁇ -2-hy droxy-3 -phenylpropanoyl] oxy ⁇ - 1 -hy droxy-9, 12- dimethoxy-10,14, 17,17-tetramethyl-l l-oxo-6 oxatetracyclo[l 1.3.1.03,10.04,7]heptadec-13- en-2-yl benzoate, XRP-6258, Jevtana).
  • Cabazitaxel in combination with prednisone may be a treatment option for hormone-refractory prostate cancer following docetaxel-based treatment;
  • larotaxel including pharmaceutically acceptable salts thereof.
  • Larotaxel may include (2 ⁇ ,5 ⁇ ,7 ⁇ , 10 ⁇ , 13 ⁇ )-4, 10-Diacetoxy- 1 -hydroxy- 13 - ⁇ [(2R,3 S)-2-hydroxy-3 - ( ⁇ [(2-methyl-2-propanyl)oxy]carbonyl ⁇ amino)-3-phenylpropanoyl]oxy ⁇ -9-oxo-5,20-epoxy- 7, 19-cyclotax-l l-en-2-yl benzoate, XRP9881, RPR109881);
  • Ortataxel may include (3aS,4R,7R,8aS,9S, 10aR,12aS, 13S, 13aS)-7, 12a-bis(acetyloxy)-4-( ⁇ (2R,3S)-3- [tert-butoxycarbonyl)amino]-2-hydroxy-5-methylhexanoyl ⁇ oxy)-9-hydroxy-5, 8a, 14, 14- tetramethyl-2,8-dioxo-3a,4,7,8,8a,9, 10,10a,12, 12a, 12b,13-dodecahydro-6, 13a- methano[ 1 ,3 ]dioxolo[8,9]cyclodeca[ 1 ,2-d] [ 1 ]benzoxet- 13 -yl benzoate);
  • milataxel including pharmaceutically acceptable salts thereof.
  • Milataxel may include (2a,5p,7p, 10p, 13a)-4-Acetoxy-13- ⁇ [(2R,3R)-3-(2-furyl)-2-hydroxy-3-( ⁇ [(2- methyl-2-propanyl)oxy]carbonyl ⁇ amino)propanoyl]oxy ⁇ -l,10-dihydroxy-9-oxo-7- (propionyloxy)-5,20-epoxytax-l l-en-2-yl benzoate, MAC-321, TL-139);
  • Tesetaxel may include (2aS,2bR,3S,4S,6S,8aR, 10S,l laS, l lbR, 13aR)-2a-(acetyloxy)-6- ⁇ [(2R,3S)-3- [(tert-butoxycarbonyl)amino]-3-(3-fluoropyridin-2-yl)-2-hydroxypropanoyl]oxy ⁇ -10- [(dimethylamino)methyl]-4-hydroxy-7, 1 lb, 14, 14-tetramethyl- 2a,2b,3,4,5,6,8a,l la, l lb,12, 13,13a-dodecahydro-2H-4,8- methano[l,3]dioxolo[3,4]cyclodeca[l,2-d][l]benzoxet-3-yl benzoate, DJ-927); or
  • abraxane (including pharmaceutically acceptable salts thereof.
  • Abraxane is a protein bound formulation of paclitaxel, also known as nanoparticle albumin-bound paclitaxel or nab-paclitaxel);
  • the chemotherapy is an antineoplastic agent, such as a platinum-based antineoplastic, optionally, wherein the antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
  • antineoplastic agent such as a platinum-based antineoplastic
  • the antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
  • An antineoplastic agent may include, for example, nucleoside analogues, antifolates, antimetabolites, enzyme inhibitors such as topoisomerase I inhibitors, anthracyclines, podophyllotoxins, alkaloids, alkylating agents, platinum compounds, antibodies, tyrosine kinase inhibitors, mTOR inhibitors, retinoids, immunomodulatory agents, histone deacetylase inhibitors.
  • enzyme inhibitors such as topoisomerase I inhibitors, anthracyclines, podophyllotoxins, alkaloids, alkylating agents, platinum compounds, antibodies, tyrosine kinase inhibitors, mTOR inhibitors, retinoids, immunomodulatory agents, histone deacetylase inhibitors.
  • an antineoplastic agent may include, for example, afatinib, aflibercept, alemtuzumab, alitretinoin, altretamine, anagrelide, arsenic trioxide, asparaginase, axitinib, azacitidine, BCG vaccine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, capecitabine, carboplatin, carmofur, carmustine, cetuximab, chlorambucil, chlormethine, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dasatinib, daunorubicin, decitabine, denileukin difti
  • Cisplatin including pharmaceutically acceptable salts thereof.
  • Cisplatin may include (SP-4-2)-diamminedichloroplatinum(II) or Platinol);
  • carboplatin including pharmaceutically acceptable salts thereof.
  • Carboplatin may include Paraplatin or cis-diammine(cyclobutane-l, l-dicarboxylate- 0,0')platinum(II));
  • dicycloplatin including pharmaceutically acceptable salts thereof.
  • Dicycloplatin may include DCP, and may be derived from carboplatin and 1,1-cyclobutane dicarboxylates);
  • Oxaliplatin (including pharmaceutically acceptable salts thereof.
  • Oxaliplatin may include Eloxatin or [(lR,2R)-cyclohexane-l,2-diamine](ethanedioato- 0,0')platinum(II));
  • Nedaplatin including pharmaceutically acceptable salts thereof.
  • Nedaplatin may include Aqupla or Diammine[(hydroxy-KO)acetato(2-)-KO]platinum);
  • triplatin tetranitrate (including pharmaceutically acceptable salts thereof.
  • Triplatin tetranitrate may include BBR3464 or Ci2H 5 4Cl2Ni40i2Pt3);
  • Phenanthriplatin (including pharmaceutically acceptable salts thereof.
  • Phenanthriplatin may include cis-[Pt(NH3)2-(phenanthridine)Cl]N03);
  • picoplatin (including pharmaceutically acceptable salts thereof.
  • Picoplatin may include azane-2-methylpyridine-platinum(2+)-dichloride);
  • pyriplatin including pharmaceutically acceptable salts thereof.
  • Pyriplatin may include cis-diammine(pyridine)chloroplatinum(II) or cDPCP); or
  • Ormaplatin including pharmaceutically acceptable salts thereof.
  • Ormaplatin may include tetraplatin or tetrachloro(l,2-cyclohexanediamine-N,N')-,(OC-6-22- (trans))platinum); or
  • satraplatin including pharmaceutically acceptable salts thereof.
  • Satraplatin may include JM216 or (OC-6-43)- bis(acetato)amminedichloro(cyclohexylamine)platinum);
  • the term "radiation therapy” refers to the medical use of ionizing radiation as part of a cancer treatment regimen to kill malignant cells that are progressing through the cell cycle (e.g., in any phase of the cell cycle).
  • the radiation therapy may be internal or external radiotherapy.
  • External radiotherapy involves targeting doses (or "fractions") of high-energy beams of radiation, either X-rays or gamma rays, to the tumor.
  • Internal radiotherapy involves positioning the source of radioactivity inside the body close to the tumor. This can be achieved in two ways: by brachytherapy or by radioisotope therapy.
  • Brachytherapy involves placing a solid source of radiation next to a tumor to give a high dose of radiotherapy.
  • Radioisotope therapy involves administration of a radioactive substance, a radioisotope, either as an intravenous injection, or as an oral capsule or liquid.
  • statin refers to any of a class of lipid-lowering drugs that reduce serum cholesterol levels by inhibiting HMG-CoA reductase, a key enzyme involved in the biosynthesis of cholesterol, the mevalonate pathway or HMG-CoA reductase pathway.
  • Non-limiting examples include atorvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and/or simvastatin, or any combinations thereof, or a combination of a statin and another agent, such as ezetimibe/simvastatin.
  • repurposed drug therapy refers to a strategy by which a new or additional value is generated from a drug by targeting a disease other than those diseases for which the drug was originally intended.
  • a repurposed drug therapy may comprise eflornithine, indinavir, metformin, or ritonavir, or a combination thereof.
  • small molecule inhibitor therapy refers to small organic molecules, peptides, antibodies, cyclic peptides and peptidomimetics that are small molecules, such as less than 10,000 Daltons (but not zero), and that act by inhibition, now known or to be developed in the medical arts.
  • a small molecule inhibitor therapy may comprise:
  • alisertib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Alisertib includes MLN8237; 4- ⁇ [9-Chloro-7-(2-fluoro-6- methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino ⁇ -2-methoxybenzoic acid);
  • BGJ398 (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • BGJ398 is a fibroblast growth factor receptor (FGFR) inhibitor and includes infigratinib; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-l- ⁇ 6-[4-(4-ethyl-piperazin-l- yl)-phenylamino]-pyrimidin-4-yl ⁇ - 1 -methyl-urea);
  • BAY1 163877 (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • BAY1163877 is a FGFR inhibitor and includes rogaratinib; 4-((4-amino-5-(7-methoxy-5-methylbenzo[b]thiophen-2-yl)-6- (methoxymethyl)pyrrolo[2,l-f][l,2,4]triazin-7-yl)methyl)piperazin-2-one); [0224] belinostat (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Belinostat includes BELEODAQ, PXD101; (2E)- N-Hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide);
  • bortezomib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Bortezomib includes VELCADE, NEOMIB, BORTEC AD ; [( 1 R)-3 -methyl- 1 -( ⁇ (2 S)-3 -phenyl-2- [(pyrazin-2- ylcarbonyl)amino]propanoyl ⁇ amino)butyl]boronic acid);
  • Bosutinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Bosutinib includes BOSULIF; 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-l-yl)propoxy]quinoline-3- carbonitrile);
  • Cabozantinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Cabozantinib includes CABMETYX, COMITRIQ; N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1, 1- dicarboxamide);
  • copanlisib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Copanlisib includes BAY 80-6946; 2-Amino-N- [7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2-c]quinazolin-5- yl]pyrimidine-5-carboxamide);
  • crizotinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Crizotinib includes XALKORI; 3-[(lR)-l-(2,6- dichloro-3-fluorophenyl)ethoxy]-5-(l-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine);
  • dasatinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Dasatinib includes BMS-354825, SPRYCEL; N- (2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4- pyrimidinyl]amino]-5-thiazole carboxamide monohydrate);
  • dovitinib including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Dovitinib includes TKI258; (3Z)-4-amino-5- fluoro-3-[5-(4-methylpiperazin-l-yl)-l,3-dihydrobenzimidazol-2-ylidene]quinolin-2-one);
  • entinostat including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Entinostat includes SNDX-275, MS-275; Pyridin-
  • erlotinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Erlotinib includes TARCEVA; N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine);
  • everolimus (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Everolimus includes RADOOl, 42-0-(2- hydroxyethyl)rapamycin; Dihydroxy-12-[(2R)-l-[(l S,3R,4R)-4-(2-hydroxyethoxy)-3- methoxycyclohexyl]propan-2-yl]- 19,30-dimethoxy- 15, 17,21 ,23 ,29,35-hexam ethyl- 11,36- dioxa-4-azatricyclo[30.3.1.0 hexatriaconta-16,24,26,28-tetraene-2,3, 10,14,20-penton]);
  • gefitinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Gefitinib includes ZD 1839, IRES S A; N-(3-chloro-
  • imatinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Imatinib includes GLEEVEC, GLIVEC, STI-571; 4-[(4- methylpiperazin-l-yl)methyl]-N-(4-methyl-3- ⁇ [4-(pyridin-3-yl)pyrimidin-2- y 1 ] amino ⁇ pheny l)b enzami de) ;
  • Ixazomib includes NINLARO, MLN2238; N2- (2,5-Dichlorobenzoyl)-N-[(lR)-l-(dihydroxyboryl)-3-methylbutyl]glycinamide);
  • lapatinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Lapatinib includes lapatinib ditosylate, TYKERB, T YVERB ; N- [3 -Chloro-4- [(3 -fluorophenyl)methoxy ]phenyl] -6-
  • Lonafarnib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Lonafarnib includes SARAS AR, SCH 66336; 4- (2- ⁇ 4-[(l lR)-3, 10-dibromo-8-chloro-6,l l-dihydro-5H-benzo[5,6]cyclohepta[l,2-b]pyridin- 11 -yl]piperidin- 1 -yl ⁇ -2-oxoethyl)piperidine- 1 -carboxamide);
  • merestinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Merestinib includes LY2801653; N-(3-Fluoro-4- ⁇ [l-methyl-6-(lH-pyrazol-4-yl)-lH-indazol-5-yl]oxy ⁇ phenyl)-l-(4-fluorophenyl)-6-methyl- 2-oxo-l,2-dihydropyridine-3-carboxamide);
  • MLN8054 (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. 4-[[9-chloro-7-(2,6-difluorophenyl)-5H- pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid);
  • olaparib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Olaparib includes AZD-2281, LY PARZA; 4-[(3-[(4- cyclopropylcarbonyl)piperazin-l-yl]carbonyl) -4-fluorophenyl]methyl(2H)phthalazin-l-one);
  • palbociclib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Palbociclib includes PD-0332991, IBRANCE; 6- Acetyl-8-cyclopentyl-5-methyl-2- ⁇ [5-(l-piperazinyl)-2-pyridinyl]amino ⁇ pyrido[2,3- d]pyrimidin-7(8H)-one);
  • pazopanib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Pazopanib includes VOTRIENT; 5-( ⁇ 4-[(2,3- Dimethyl-2H-indazol-6-yl)methylamino]pyrimidin-2-yl ⁇ amino)-2- methy lb enzene sulf onami de) ;
  • pexidartinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Pexidartinib includes PLX-3397; 5-[(5-Chloro-lH- pyrrolo[2,3-b]pyridin-3-yl)methyl]-N- ⁇ [6-(trifluoromethyl)-3-pyridinyl]methyl ⁇ -2- pyridinamine);
  • Rapamycin (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Rapamycin includes sirolimus, RAPAMUNE; (1R, 9S, 12S, 15R, 16E, 18R,19R,21R,23S,24E,26E,28E,
  • sapanisertib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • sorafenib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Sorafenib includes sorafenib tosylate, NEXAVAR; 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2- carboxamide);
  • sunitinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Sunitinib includes SU11248, SUTENT; N-(2- diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-lH-indol-3-ylidene)methyl]-2,4-dimethyl-lH- py rrol e-3 -carb oxami de);
  • tipifarnib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Tipifarnib includes Rl 15777, ZARNESTRA; (+)- 6-[(R)-Amino-(4-chlorophenyl)-(3-methylimidazol-4-yl)methyl]-4-(3-chlorophenyl)-l- methylquinolin-2-one);
  • Vandetanib includes CAPRELSA, ZD6474; N-(4- bromo-2-fluorophenyl)-6-methoxy-7-[(l-methylpiperidin-4-yl)methoxy]quinazolin-4- amine);
  • vistusertib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof.
  • Vistusertib includes AZD2014; 3-[2,4-Bis((3S)-3- methylmorpholin-4-yl)pyrido[5,6-e]pyrimidin-7-yl]-N-methylbenzamide); or
  • Vorinostat includes suberanilohydroxamic acid, ZOLINZA; N-Hydroxy-N'-phenyloctanediamide);
  • a therapeutic antibody therapy refers to any antibody, now known or to be developed in the medical arts, which can be administered to a subject as an active agent, including derivatives and fragments thereof, or antigen-specific ligand molecules, such as antibody Fab fragments, or antibody Fc fragments, synthetic receptors, soluble receptors, that selectively bind a target antigen.
  • a therapeutic antibody therapy may comprise cetuximab, ritixumab, bevacizumab, ranibizumab, trastuzumab, or panitumumab, fragments thereof, or a combination thereof.
  • an immunotherapy refers to a therapy for a disease that relies on an immune response.
  • an immunotherapy may comprise nivolumab, durvalumab, pembrolizumab, atezolizumab, ipilimumab, tremelimumab, CA- 170, EO-PV-01, or a tumor cell-derived vaccine therapy, or any combinations thereof.
  • a compound of Formula (I) may be administered alone or in combination with a therapy as described herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic treatments, virus-based therapies, surgeries, chemotherapies, such as a taxane-based chemotherapy agent, an antineoplastic agent, such as a platinum-based antineoplastic agent, radiation therapies, statin treatments, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combination thereof to a subject in need.
  • a therapy including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic treatments, virus-based therapies, surgeries, chemotherapies, such as a taxane-based chemotherapy agent, an antineoplastic agent, such as a platinum-based antineoplastic agent, radiation therapies, statin treatments, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combination thereof to a subject in need.
  • the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
  • a medicament for the treatment or inhibition of cancer may be prepared by providing a compound of Formula (I) in a composition.
  • a medicament for the treatment or inhibition of cancer, such as bladder cancer or prostate cancer may be prepared by providing a compound of Formula (I) in combination with one or more of the therapies described herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic treatments, virus-based therapies, surgeries, chemotherapies, such as a taxane-based chemotherapy agent, an antineoplastic agent, such as a platinum-based antineoplastic agent, radiation therapies, statin treatments, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen depriv
  • a product combination comprising a compound of Formula (I) in combination with a one or more of the therapies as described herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic treatments, virus-based therapies, surgeries, chemotherapies, such as a taxane-based chemotherapy agent, an antineoplastic agent, such as a platinum-based antineoplastic agent, radiation therapies, statin treatments, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy may be provided or administered to a subject in need.
  • an androgen deprivation therapies such as a taxane-based chemotherapy agent
  • an antineoplastic agent such as a platinum-based antineo
  • compositions described herein may be formulated for oral, intranasal, or parenteral administration.
  • Oral administration may include formulation of the compositions for administration to the oral cavity, including for administration to the digestive tract, the buccal lining, or the respiratory tract through the oral cavity, for example, formulation of the compositions as a tablet, pill, capsule, pellet, dragee, gummy, powder, softgel, liquid, syrup, suspension, solution, or inhalable composition.
  • Intranasal administration may include formulation for administration by the nasal cavity, and may include drops, spray, insufflation, or inhalable compositions.
  • Parenteral administration may include, for example, intraperitoneal, infusion, intramuscular, subcutaneous, intradermal, or intravenous injection.
  • compositions described herein further include pharmaceutically acceptable carriers and excipients, depending on the desired delivery or mode of administration format.
  • the pharmaceutically acceptable carrier may comprise glycerol. In some embodiments, the pharmaceutically acceptable carrier may comprise a mixture of triacylglycerols, monoacylglycerols, diacylglycerols, and/or free fatty acids. In some embodiments, the pharmaceutically acceptable carrier may comprise a mixture of triacylglycerols. In some embodiments, the pharmaceutically acceptable carrier may comprise a mixture of long chain (Cs-Cso) saturated or unsaturated fatty acids, fatty alcohols, or glyceryl esters of one or more fatty acids. In some embodiments, the long chain saturated or unsaturated fatty acids may comprise from 10 to 40 carbon atoms (C10-C40).
  • the long chain saturated or unsaturated fatty acids may comprise from 10 to 20 carbon atoms (C10-C20).
  • the mixture of triacylglycerols, monoacylglycerols, diacylglycerols, and/or free fatty acids can be an oil or wax at room temperature.
  • each long chain saturated or unsaturated fatty acid is selected from caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linolenic acid (including alpha-linolenic acid and/or gamma- linolenic acid), linoleic acid, arachidic acid, ricinoleic acid, dihydroxystearic acid, behenic acid, ligoceric acid, erucic acid, and/or godonic acid.
  • each long chain saturated or unsaturated fatty acid is selected from (Z)-9-octadecenoic acid, oleic acid (8CI), 9-cis-octadecenoic acid, 9Z-octadecenoic acid, B 115, Clear FRAC EF, Crodacid O-P, Crossential O 94, D 100, D 100 (fatty acid), Edenor ⁇ 05, Edenor FTi05, Emersol 205, Emersol 211, Emersol 213 F, Emersol 214 F, Emersol 233, Emersol 6313 F, Extra Oleic 80R, Extra Oleic 90, Extra Oleic 99, Extra Olein 80, Extra Olein 90, Extra Olein 90R, Extra Olein A 1981, Industrene 105, Lunac O-CA, Lunac O-LL, Lunac O-P, Lunac O-V, Lunac OA, NAA 35, NAA 38, Neo-Fat 92-04, Oleine 750
  • the pharmaceutically acceptable carrier may comprise a mixture of triacylglycerols having long chain saturated or unsaturated fatty acids including alpha-linolenic acid, arachidic acid, behenic acid, capric acid, caproic acid, caprylic acid, dihydroxystearic acid, erucic acid, gondonic acid, lauric acid, lignoceric acid, linoleic acid, myristic acid, oleic acid, palmitic acid, palmitoleic acid, ricinoleic acid, and/or stearic acid.
  • triacylglycerols having long chain saturated or unsaturated fatty acids including alpha-linolenic acid, arachidic acid, behenic acid, capric acid, caproic acid, caprylic acid, dihydroxystearic acid, erucic acid, gondonic acid, lauric acid, lignoceric acid, linoleic acid, myristic acid, oleic acid, palmitic acid, palm
  • the pharmaceutically acceptable carrier may comprise a mixture of triacylglycerols obtained from the seeds of Ricinus communis L., Euphorbiaceae; Gossypium herbaceum L., Malvaceae; Vitis vinifera L., Vitaceae; Arachis hypogaea L., Leguminosae; Brassica napus L., Brassicaceae; Brassica rapa L., Brassicaceae; Brassica juncea L., Brassicaceae; Helianthus annuus L., Compositae; Carthamus tinctorius L., Compositae; Sesamum indicum L., Pedaliaceae; or Glycine max L., Fabaceae; or obtained from the kernels of Cocos nucifera L., Palmae; or obtained from the grain of Zea mays L., Gramineae; or obtained from the fruit of Olea europaea L, Oleaceae; Elae
  • pharmaceutically acceptable carrier may comprise a mixture of triacylglycerols, where the mixture of triacylglycerols have a fatty acid content comprising 44-75% linoleic acid, 14-35% oleic acid, 3-10% palmitic acid, 1-8% stearic acid, 0.6-4% arachidic acid, and 1% behenic acid.
  • the pharmaceutically acceptable carrier may comprise an oil selected from castor oil, coconut oil, corn oil, cottonseed oil, grapeseed oil, olive oil, palm oil, peanut oil, rapeseed oil, canola oil, safflower oil, sesame oil, soybean oil, or sunflower oil, or any combinations thereof.
  • the pharmaceutically acceptable carrier may comprises a mixture of triacylglycerols and further comprise dimethyl sulfoxide.
  • Dimethyl sulfoxide may be used as a pharmaceutically acceptable carrier to facilitate the uptake of a compound of Formula (I), alone or in combination with an additional therapy as described herein, into cells or tissues of a subject.
  • Dimethyl sulfoxide may be used as a pharmaceutically acceptable carrier to facilitate absorption of a compound of Formula (I) in the gastrointestinal tract of a subject.
  • the pharmaceutically acceptable carrier may comprise propylene glycol.
  • the pharmaceutically acceptable carrier may comprise esters of propylene glycol.
  • the ester of propylene glycol can be propylene glycol monocaproate, propylene glycol monocaprylate, propylene glycol monodecanoate, propylene glycol monolaurate, propylene glycol monomyri state, propylene glycol monopalmitate, propyleneglycol monostearate, propylene glycol monooleate, propylene glycol monolinolenate, propylene glycol dicaproate, propylene glycol dicaprylate, propylene glycol didecanoate, propylene glycol dilaurate, propylene glycol dimyristate, propylene glycol dipalmitate, propyleneglycol distearate, propylene glycol dioleate, or propylene glycol dilinolenate, or any
  • the pharmaceutically acceptable carrier may comprise esters of polyethylene glycol.
  • the ester of polyethylene glycol can comprise PEG-8, PEG-10, PEG-25, PEG-55, PEG 75, PEG 120, or PEG 660 monocaproate or dicaproate; PEG-8, PEG-10, PEG-25, PEG-55, PEG 75, PEG 120, or PEG 660 monocaprylate or dicaprylate; PEG-8, PEG-10, PEG-25, PEG-55, PEG 75, PEG 120, or PEG 660 monodecanoate or didecanoate; PEG-8, PEG-10, PEG-25, PEG-55, PEG 75, PEG 120, or PEG 660 monolaurate or dilaurate; PEG-8, PEG-10, PEG-25, PEG-55, PEG 75, PEG 120, or PEG 660 monomyristate or dimyristate; PEG-8, PEG-10, PEG-25, PEG-55, PEG 75, P
  • the pharmaceutically acceptable carrier may comprises a pegylated glyceride.
  • pegylated glycerides comprise GELUCIRE ® 44/14 (lauroyl macrogol-32 glycerides) and/or GELUCIRE ® 50/13 (stearoyl macrogol-32 glycerides).
  • Ri and R2 can be the same. In some embodiments, each of Ri and R2 can be different.
  • the fatty acid ester can be methyl caproate, ethyl caproate, propyl caproate, isopropyl caproate, butyl caproate, sec-butyl caproate, tert-butyl caproate, pentyl caproate, hexyl caproate, heptyl caproate, octyl caproate, nonyl caproate, or decyl caproate, or any combination thereof.
  • the fatty acid ester can be methyl caprylate, ethyl caprylate, propyl caprylate, isopropyl caprylate, butyl caprylate, sec-butyl caprylate, tert-butyl caprylate, pentyl caprylate, hexyl caprylate, heptyl caprylate, octyl caprylate, nonyl caprylate, or decyl caprylate, or any combination thereof.
  • the fatty acid ester can be methyl decanoate, ethyl decanoate, propyl decanoate, isopropyl decanoate, butyl decanoate, sec-butyl decanoate, tert-butyl decanoate, pentyl decanoate, hexyl decanoate, heptyl decanoate, octyl decanoate, nonyl decanoate, or decyl decanoate, or any combination thereof.
  • the fatty acid ester can be methyl laurate, ethyl laurate, propyl laurate, isopropyl laurate, butyl laurate, sec-butyl laurate, tert-butyl laurate, pentyl laurate, hexyl laurate, heptyl laurate, octyl laurate, nonyl laurate, or decyl laurate, or any combination thereof.
  • the fatty acid ester can be methyl myristate, ethyl myristate, propyl myristate, isopropyl myristate, butyl myristate, sec-butyl myristate, tert-butyl myristate, pentyl myristate, hexyl myristate, heptyl myristate, octyl myristate, nonyl myristate, or decyl myristate, or any combination thereof.
  • the fatty acid ester can be methyl palmitate, ethyl palmitate, propyl palmitate, isopropyl palmitate, butyl palmitate, sec-butyl palmitate, tert-butyl palmitate, pentyl palmitate, hexyl palmitate, heptyl palmitate, octyl palmitate, nonyl palmitate, or decyl palmitate, or any combination thereof.
  • the fatty acid ester can be methyl stearate, ethyl stearate, propyl stearate, isopropyl stearate, butyl stearate, sec-butyl stearate, tert-butyl stearate, pentyl stearate, hexyl stearate, heptyl stearate, octyl stearate, nonyl stearate, or decyl stearate, or any combination thereof.
  • the fatty acid ester can be methyl oleate, ethyl oleate, propyl oleate, isopropyl oleate, butyl oleate, sec-butyl oleate, tert-butyl oleate, pentyl oleate, hexyl oleate, heptyl oleate, octyl oleate, nonyl oleate, or decyl oleate, or any combination thereof.
  • the fatty acid ester can be methyl linolenate, ethyl linolenate, propyl linolenate, isopropyl linolenate, butyl linolenate, sec-butyl linolenate, tert-butyl linolenate, pentyl linolenate, hexyl linolenate, heptyl linolenate, octyl linolenate, nonyl linolenate, or decyl linolenate, or any combinations thereof.
  • the pharmaceutically acceptable carrier may comprise a sorbitan ester.
  • the sorbitan ester can comprise sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, or sorbitan isostearate, or any combinations thereof.
  • the sorbitan ester can comprise Span 20, Span 40, Span 60, Span 80, Span 83, Span 85, Span 120, or any combination thereof.
  • the pharmaceutically acceptable carrier may comprise a polysorbate.
  • the polysorbate can comprise polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene (4) sorbitan monopalmitate, or polyoxyethylene (4) sorbitan monostearate, or polyoxyethylene (4) sorbitan monooleate, or any combinations thereof.
  • the polysorbate can comprise Tween 20, Tween 21, Tween 40, Tween 60, Tween 61, Tween 65, or Tween 80, or any combination thereof.
  • the concentration of a compound of Formula (I) dissolved or suspended in the at least one pharmaceutically acceptable carrier that comprises a mixture of triacylglycerols, monoacylglycerols, diacylglycerols, and/or free fatty acids may vary from about or any number in between 1-1000 mg of a compound of Formula (I) per mL of pharmaceutically acceptable carrier.
  • the concentration of a compound of Formula (I) ranges from 1, 2, 5, 7, 10, 12, 15, 17, 20, 22, 25, 27, 30, 32, 35, 37, 40, 42, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg/mL or within a range defined by any two of the aforementioned values.
  • the concentration of a therapy agent that is used in combination with a compound of Formula (I) ranges from 1, 2, 5, 7, 10, 12, 15, 17, 20, 22, 25, 27, 30, 32, 35, 37, 40, 42, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg/mL or within a range defined by any two of the aforementioned values.
  • compositions comprising a compound of Formula (I), at least one pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
  • the composition further comprises an additional therapy as described herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus- based therapies, surgeries, chemotherapies, antineoplastic therapies, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapy or antineoplastic therapy is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
  • the at least one pharmaceutically acceptable excipient can be selected from a sugar, a starch, a cellulose preparation, silicon dioxide aerosol, gelatin, calcium phosphate dibasic, sodium lauryl sulfate, magnesium stearate, sodium stearyl fumarate, talc, polyethylene glycol, or polyvinylpyrrolidone, or any combinations thereof.
  • the at least one pharmaceutically acceptable excipient can be selected from a pregelatinized starch, partially pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, a lactose-cellulose blend, methyl cellulose, or silicon dioxide aerosol, or any combinations thereof.
  • the at least one pharmaceutically acceptable excipient can be selected from microcrystalline cellulose, lactose, sucrose, starch powder, maize starch or derivatives thereof, cellulose esters of alkanoic acids, cellulose alkyl esters, stearic acid, magnesium oxide, sodium and/or calcium salts of phosphoric and sulfuric acids, acacia gum, sodium alginate, or polyvinyl alcohol, or any combinations thereof.
  • the at least one pharmaceutically acceptable excipient can be selected from dextrose, mannitol, lactose monohydrate, lecithin, albumin, sodium glutamate, cysteine hydrochloride, croscarmellose sodium, sodium starch glycolate, hydroxypropyl cellulose, poloxamer, sodium lauryl sulfate, or colloidal silicon dioxide, or any combination thereof.
  • Poloxamers comprise, for example, poloxamer 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403, 407, poloxamer 105 benzoate, or poloxamer 182 dibenzoate 407 or any combination thereof.
  • the at least one pharmaceutically acceptable excipient can comprise microcrystalline cellulose.
  • the at least one pharmaceutically acceptable excipient can be an aluminometasilicate, such as sodium aluminometasilicate, magnesium aluminometasilicate, calcium aluminometasilicate, potassium aluminometasilicate, or lithium aluminometasilicate or any combination thereof.
  • aluminometasilicate such as sodium aluminometasilicate, magnesium aluminometasilicate, calcium aluminometasilicate, potassium aluminometasilicate, or lithium aluminometasilicate or any combination thereof.
  • the amount of the pharmaceutically acceptable excipient may vary from or any number in between 1% to 75% by weight of the total pharmaceutical composition. In some embodiments, the amount of excipient ranges from or any number in between 1-5%, 2- 7%, 5-10%, 7-12%, 10-15%, 12-17%, 15%-20%, 17%-22%, 20%-25%, 22%-27%, 25%- 30%, 27%-32%, 30%-35%, 32%-37%, 35%-40%, 37%-42%, 40%-45%, 40-50%, 45-55%, 50-60%), 55-65%), 60-70%), or 65-75%) by weight of the total pharmaceutical composition or within a range defined by any two of the aforementioned amounts.
  • the amount of excipient is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 75% of the weight of the total pharmaceutical composition or within a range defined by any two of the aforementioned amounts. In some embodiments, the amount of excipient is less than 5% of the weight of the total pharmaceutical composition but not zero.
  • the amounts of excipient can be determined by the dosage of a compound of Formula (I), alone or in combination with an androgen deprivation therapies, anti-estrogen therapies, biologic treatments, virus-based therapies, surgeries, chemotherapies, antineoplastic therapies, radiation therapies, statin treatments, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combination thereof, optionally, wherein the chemotherapy or antineoplastic therapy is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy, and the dosage form size of the total pharmaceutical composition.
  • the dosage form size of the total pharmaceutical composition is 175 mg. In some embodiments disclosed herein the dosage form size of the total pharmaceutical composition is 350 mg. In some embodiments disclosed herein the dosage form size of the total pharmaceutical composition is 700 mg.
  • the preferred dosage form size range of the total pharmaceutical composition is from 50 mg to 1500 mg, more typically from 100 mg to 1000 mg, more typically from 175 mg to 700 mg, with the preferred typical dosage form size of the total pharmaceutical composition being 175 mg, 350 mg, or 700 mg or within a range defined by any two of the aforementioned amounts.
  • the at least one pharmaceutically acceptable excipient can be selected from binders, disintegrants, surfactants, or stabilizers. Any one or more of the excipients (including binders, disintegrants, surfactants, or stabilizers) can be appropriate in the pharmaceutical composition containing a compound of Formula (I), alone or in combination with an additional therapy, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies, antineoplastic therapies radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapy or antineoplastic therapy is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy and at least one pharmaceutically acceptable carrier in accordance with the disclosure herein, provided that the compound of Formula (I), alone or in combination with an
  • the at least one pharmaceutically acceptable excipient can comprise at least one or more binders.
  • the at least one or more binders can be used, for example, to impart cohesive qualities to a pharmaceutical formulation comprising the compound of Formula (I), alone or in combination with one or more an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies, antineoplastic therapies, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein chemotherapy or antineoplastic therapy is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy and thus permit the resulting dosage form to remain intact during formulation of capsules, tablets, film coated tablets, caplets, gel caps, pill pellets, or beads, suitable for oral administration to a subject.
  • the one or more binders are selected from microcrystalline cellulose, gelatin, sugars (including, for example, sucrose, glucose, dextrose and maltodextrin), polyethylene glycol, waxes, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, povidone, cellulosic polymers (including, for example, hydroxypropyl cellulose (UPC), hydroxypropyl methylcellulose (UPMC), methyl cellulose, hydroxyethyl cellulose), or hydroxypropyl cellulose (HPC), or any combinations thereof.
  • sugars including, for example, sucrose, glucose, dextrose and maltodextrin
  • polyethylene glycol waxes
  • waxes natural and synthetic gums
  • polyvinylpyrrolidone pregelatinized starch
  • povidone povidone
  • cellulosic polymers including, for example, hydroxypropyl cellulose (UPC), hydroxypropyl methylcellulose (UPMC), methyl
  • the at least one pharmaceutically acceptable excipient can comprise one or more disintegrants.
  • the at least one or more disintegrants can be used, for example, to facilitate disintegration of a pharmaceutical composition after oral administration.
  • the at least one or more disintegrants are selected from starches, clays, celluloses, algins, gums, or crosslinked polymers or any combinations thereof.
  • the one or more disintegrants are selected from crosslinked polyvinylpyrrolidone (PVP-XL), sodium starch glycolate, alginic acid, methacrylic acid DYB, microcrystalline cellulose, crospovidone, polacriline potassium, sodium starch glycolate, starch, pregelatinized starch, or croscarmellose sodium or any combinations thereof.
  • PVP-XL crosslinked polyvinylpyrrolidone
  • sodium starch glycolate alginic acid
  • methacrylic acid DYB microcrystalline cellulose
  • crospovidone crospovidone
  • polacriline potassium sodium starch glycolate
  • starch pregelatinized starch
  • the at least one pharmaceutically acceptable excipient can comprise one or more surfactants.
  • the at least one or more surfactants can be used, for example, as a wetting agent.
  • the at least one or more surfactants can be used, for example, to improve the permeation and/or bioavailability of the compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies, antineoplastic therapy, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combinations thereof, optionally, wherein the chemotherapy or antineoplastic therapy is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
  • the at least one or more surfactants are selected from anionic surfactants, non-ionic surfactants, or zwitterionic surfactants or any mixture thereof.
  • the one or more surfactants are selected from poly(oxyethylene) sorbitan fatty acid ester, poly(oxyethylene) stearate, poly(oxyethylene) alkyl ether, polyglycolated glyceride, poly(oxyethylene) castor oil, sorbitan fatty acid ester, poloxamer, fatty acid salt, bile salt, alkyl sulfate, lecithin, mixed micelle of bile salt and lecithin, glucose ester vitamin E TPGS (D-a-tocopheryl polyethylene glycol 1000 succinate), or sodium lauryl sulfate or any combinations thereof. 4. Stabilizers
  • the at least one pharmaceutically acceptable excipient can comprise one or more stabilizers.
  • the at least one or more stabilizers are selected from alkanizing agents, chelating agents, photoprotectants, or antioxidants or any combinations thereof.
  • the alkanizing agent is selected from alkali metal salt additives or an alkaline earth metal salt additive or any combinations thereof.
  • Alkali metal salt additives suitable for use in some embodiments can comprise, for example, sodium carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate or other suitable alkali metal salts or any combinations thereof.
  • Alkaline earth metal salt additives can comprise, for example, calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, or aluminum magnesium hydroxide or any combinations thereof.
  • the chelating agent comprises disodium EDTA, edetic acid, or citric acid, or any combination thereof.
  • a photoprotectant can be used, for example, to protect the pharmaceutical composition from the chemical or physical effects of light.
  • the photoprotectant is selected from titanium oxide, ferric oxide, or zinc oxide or any combination thereof.
  • the antioxidant is selected from butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulfite, propyl gallate, tocopherol, citric acid, malic acid, or ascorbic acid, or any mixtures thereof.
  • a compound of Formula (I) may be formulated as a pharmaceutical composition, alone or in combination with an additional therapy as disclosed herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy suitable for oral administration to a subject.
  • an androgen deprivation therapies such as taxane-based chemotherapy agents
  • an antineoplastic agent such as a platinum-based antineoplastic agents
  • radiation therapies stat
  • the pharmaceutical composition is formulated for oral ingestion by a subject as a tablet, pill, capsule, granule, gummy, dragee, liquid, gel, syrup, slurry, spray, or suspension.
  • the composition is in the form of a tablet, a film coated tablet, a gel cap, a caplet, a pellet, or a bead.
  • the pharmaceutical composition is in the form of a capsule having a dissolvable enclosure for carrying the compound of Formula (I), alone or in combination with an additional therapy described herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormone deprivation therapy, rmonal therapy, is not a hormone replacement therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy and one or more pharmaceutically acceptable carriers and/or excipients.
  • a capsule is made of gelatin.
  • the pharmaceutical composition is in the form of
  • compositions for oral administration may be obtained by combining a compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy, with one or more pharmaceutically acceptable carriers and/or excipients, optionally grinding the resulting mixture, and processing the mixture, to obtain tablets, pills, capsules, granules, dragees, a liquid, a gel, a syrup,
  • compositions comprising a compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti- estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy may be manufactured by mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.
  • the pharmaceutical composition may comprise a coating, for example, a film coating.
  • coating preparations can comprise, for example, a film-forming polymer, or a plasticizer.
  • film-forming polymers suitable for use in the embodiments described herein comprise hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl pyrrolidine, or starches or any combinations thereof.
  • plasticizers suitable for use in the embodiments described herein comprise polyethylene glycol, tributyl citrate, dibutyl sebecate, or acetylated monoglyceride or any combinations thereof.
  • Dyestuffs or pigments may be added to the pharmaceutical composition or to coatings for the pharmaceutical composition for identification or to characterize different combinations of active compound doses.
  • concentrated sugar solutions may be used, which may optionally comprise gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures or any combinations thereof.
  • Dyestuffs or pigments may be added for identification or to characterize different dosage amounts of a compound of Formula (I), or the one or more additional therapies included in the pharmaceutical composition, and including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
  • Non-limiting examples of dyestuffs and pigments suitable for use in the embodiments described herein comprise iron oxides of various colors, lake dyes of many colors, or titanium
  • the pharmaceutical composition is formulated for intranasal administration.
  • the composition is formulated as a drop, a spray, or an inhalant for administration to the nasal cavity.
  • a compound of Formula (I) is formulated for intranasal administration alone or in combination with an additional therapy described herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies, such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti
  • the pharmaceutical composition is formulated for parenteral administration.
  • the composition is formulated as a solution for intraperitoneal, infusion, intramuscular, subcutaneous, intradermal, or intravenous injection.
  • a compound of Formula (I) is formulated for parenteral administration alone or in combination with an additional therapy described herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies, such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy,
  • the pharmaceutical composition may be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing a compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
  • chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen depri
  • the pack may for example include metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • Such notice for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • the pharmaceutical composition comprising a compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy, may be placed in an appropriate container, and labeled for treatment or inhibition of an indicated condition, such as for treatment or inhibition of a cancer such as bladder cancer or prostate cancer.
  • the pharmaceutical compositions comprising the compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy can be stable for at least, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 24 months, 36 months, or 48 months or within a range defined by any two of
  • compositions comprising the compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus- based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy and methods of using such compositions to inhibit, delay, treat, or prevent bladder or prostate cancer cell growth or bladder or prostate cancer in a subject in need thereof.
  • chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antine
  • compositions comprising a compound of Formula (I) have significant anti-cancer properties for oral administration to subjects in need of anti-cancer therapy.
  • the primary mechanism of cytotoxic action of pharmaceutical compositions comprising a compound of Formula (I) is due to redox-cycling and electrophilic arylation.
  • a compound of Formula (I) may be reduced by electron transfer from flavoprotein to a semiquinone radical, which can, in turn, reduce oxygen to superoxide. The resulting superoxide may consequently be converted into hydrogen peroxide, hydroxyl radicals, and/or peroxynitrite, all of which are highly reactive oxygen species (ROS) with potent cytotoxic and tumoricidial effects.
  • ROS highly reactive oxygen species
  • an additional antitumor mechanism of pharmaceutical compositions including a compound of Formula (I) may involve direct arylation of intracellular thiols leading to depletion of glutathione (GSH). Depletion of GSH may ultimately result in alkylation of cellular macromolecules and in their inactivation. Such activities may contribute to the tumoricidial effects of pharmaceutical compositions including a compound of Formula (I).
  • an additional antitumor mechanism for pharmaceutical compositions including a compound of Formula (I) may involve inhibition of microtubule polymerization and binding to tubulin. Because one of the defining characteristics of cancer cells is a significantly increased rate of cell cycle entry and/or mitosis, cancer cells are more vulnerable to agents that affect microtubule polymerization than normal cells.
  • the compound of Formula (I) may recognize the colchicine binding site of tubulin and inhibit in vitro tubulin polymerization.
  • compositions comprising a compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy exhibit significant and unexpectedly improved (for example, synergy may be obtained) effects for inhibiting, delaying, and preventing the growth of cancer such as bladder cancer or prostate cancer when the pharmaceutical compositions including a compound of Formula (I), alone or in combination with one or more of an androgen therapies, biologic
  • chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin treatments, repurposed
  • composition comprising a compound of Formula (I) is provided in combination with the additional therapies described herein, an unexpected and surprising reduction, delay, or inhibition in cancer cell growth, such as bladder cancer cell growth or prostate cancer cell growth, is realized.
  • compositions comprising a compound of Formula (I) are provided in combination or in co-administration with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
  • chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein can be used in combination with one or more therapies, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy.
  • therapies including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent such as
  • Some alternatives disclosed herein relate to a method of ameliorating, inhibiting or treating cancer such as bladder cancer or prostate cancer that can comprise administering or providing to a subject suffering from cancer such as bladder cancer or prostate cancer a pharmaceutical composition comprising a compound of Formula (I) in combination with one or more additional agents (referred to as "combination therapy").
  • a pharmaceutical composition comprising a compound of Formula (I) is administered to a patient instead of anti-AR drugs to prevent recurrence in patients previously experiencing a therapy for cancer, such as bladder cancer (including high risk non muscle-invasive bladder cancer) or prostate cancer.
  • a pharmaceutical composition comprising a compound of Formula (I) is administered to patients who have become resistant to cancer therapies, such as resistant to enzalutamide or to other AR antagonists and still display AR activity.
  • a pharmaceutical composition comprising a compound of Formula (I) may be used in combination with an additional agent as described herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
  • an additional agent including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic
  • a composition comprising a compound of Formula (I), alone or in combination with of one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
  • chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
  • the methods include selecting a subject who is suffering from cancer such as bladder cancer or prostate cancer and administering a composition comprising a compound of Formula (I).
  • the subject is selected who has previously received a therapy for cancer, such as bladder cancer (including high risk bladder cancer) or prostate cancer.
  • the subject is selected who is in need of cancer treatment.
  • the subject is selected who has developed a recurrence of cancer.
  • the subject is selected who has developed a resistance to cancer treatments, such as resistance to enzalutamide or other androgen receptor antagonists and yet still displays androgen receptor activity.
  • a subject is selected who has any combination of the aforementioned selection criteria.
  • the methods comprise selecting a subject as described herein who is suffering from cancer such as bladder cancer or prostate cancer, and administering a composition including a compound of Formula (I) in combination with an androgen deprivation therapy (ADT).
  • ADT comprises a surgical method of ADT, such as surgical orchiectomy.
  • the ADT comprises a pharmaceutical-based ADT comprising administration of an agent, comprising orteronel, cyproterone acetate, flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, galeterone, abiraterone, finasteride, ethylstilbestrol (DES), megestrol acetate, fosfestrol, estramustine phosphate, leuprolide, triptorelin, goserelin, histrelin, buserelin, abarelix, degarelix, or derivatives, salts, or analogues thereof, or any combinations thereof.
  • an agent comprising orteronel, cyproterone acetate, flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, galeterone, abiraterone, finasteride, ethylstilbestrol (DES), megestrol a
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with surgical orchiectomy.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with orteronel.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with cyproterone acetate.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with flutamide.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with nilutamide.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with bicalutamide. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with enzalutamide. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with apalutamide. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with galeterone. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with abiraterone.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with finasteride. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ethylstilbestrol (DES). In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with megestrol acetate. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with fosfestrol. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with estramustine phosphate.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with leuprolide. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with triptorelin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with goserelin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with histrelin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with buserelin.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with abarelix. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with degarelix.
  • the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with an anti-estrogen therapy (anti-ER therapy).
  • anti-ER therapy comprises a surgical method of anti-ER therapy, e.g., surgical ovariectomy.
  • the anti-ER therapy comprises a pharmaceutical-based anti-ER therapy, comprising administration of tamoxifen, clomifene, ormeloxifene, toremifene, lasofoxifene, ospemifene, raloxifene, fulvestrant, brilanestrant, elacestrant, anastrozole, letrozole, testolactone, exemestane, or derivatives, salts, or analogues thereof, or combinations thereof.
  • a pharmaceutical-based anti-ER therapy comprising administration of tamoxifen, clomifene, ormeloxifene, toremifene, lasofoxifene, ospemifene, raloxifene, fulvestrant, brilanestrant, elacestrant, anastrozole, letrozole, testolactone, exemestane, or derivatives, salts, or analogues thereof, or combinations thereof.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ovariectomy. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with tamoxifen. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with clomifene. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ormeloxifene. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with toremifene.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with lasofoxifene. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ospemifene. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with raloxifene. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with fulvestrant. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with brilanestrant.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with elacestrant. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with anastrozole. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with letrozole. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with testolactone. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with exemestane.
  • the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a biologic.
  • a biologic comprises Bacillus Calmette-Guerin (BCG) vaccine, sargramostim, filgrastim, pegfilgrastim, recombinant interleukin-12, or interferon alpha, or a combination thereof.
  • BCG Bacillus Calmette-Guerin
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with Bacillus Calmette-Guerin (BCG) vaccine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with sargramostim. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with filgrastim. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pegfilgrastim. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with recombinant interleukin-12. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with interferon alpha.
  • BCG Bacillus Calmette-Guerin
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with s
  • the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a virus-based therapy.
  • a virus-based therapy comprises use of a reovirus, bunyavirus, flavivirus, rubivirus, filovirus, arenavirus, arterivirus, calicivirus, a retrovirus, an adenoviral vector, (including the oncolytic adenovirus vector CG0070 (Cold Genesys)), or a Coxsackievirus A21 (CVA21; CAVATAK, Viralytics), or a combination thereof.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with reovirus.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with bunyavirus.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with flavivirus.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with rubivirus.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with filovirus.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with arenavirus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with arterivirus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with calicivirus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with a retrovirus.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with an adenoviral vector (comprising the oncolytic adenovirus vector CG0070 (Cold Genesys)).
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with a Coxsackievirus A21 (CVA21; CAVATAK, Viralytics).
  • the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a chemotherapy, optionally, wherein the chemotherapeutic agent or chemotherapy is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
  • a chemotherapy comprises gemcitabine, cyclophosphamide, methotrexate, 5- fluorouracil, doxorubicin, mustine, vincristine, procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, etoposide, epirubicin, capecitabine, methotrexate, folinic acid, lenalidomide, pemetrexed, azacitidine and analog decitabine, mitomycin C, apaziquone, eribulin, valrubicin, vinflunine, pirarubicine, pralatrexate, temsirolimus, sirolimus, ifosfamide, irinotecan, rubitecan, or AZD4877, or combinations thereof.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with gemcitabine.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with cyclophosphamide.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with methotrexate.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with 5-fluorouracil.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with doxorubicin.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with mustine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with vincristine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with procarbazine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with prednisolone. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with bleomycin.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with vinblastine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with dacarbazine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with etoposide. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with epirubicin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with capecitabine.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with methotrexate. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with folinic acid. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with lenalidomide. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pemetrexed. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with azacitidine.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with decitabine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with mitomycin C. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with apaziquone. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with eribulin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with valrubicin.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with vinflunine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pirarubicine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pralatrexate. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with temsirolimus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with sirolimus.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ifosfamide. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with irinotecan. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with rubitecan. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with AZD4877.
  • the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a taxane-based chemotherapy agent.
  • a taxane-based chemotherapy agent comprises docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or combinations, analogues, derivatives, emulsions, pro-drugs, and/or lipid conjugates, or polymers thereof or any combination thereof.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with docetaxel. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with paclitaxel. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with cabazitaxel. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with 5- larotaxel. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ortataxel.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with milataxel. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with tesetaxel. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with abraxane.
  • the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a platinum-based antineoplastic agent.
  • a platinum-based antineoplastic agent comprises cisplatin, carboplatin, dicycloplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, or satraplatin, or analogues or derivatives thereof or any combinations thereof.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with cisplatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with carboplatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with dicycloplatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with 5- oxaliplatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with nedaplatin.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with triplatin tetranitrate. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ormaplatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with phenanthriplatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with picoplatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pyriplatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with satraplatin.
  • the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a radiation therapy.
  • radiation therapy comprises internal or external radiotherapy.
  • internal radiotherapy comprises positioning the source of radioactivity inside the body close to the tumor through brachytherapy or radioisotope therapy.
  • external radiotherapy comprises targeting doses of high- energy beams of radiation to the tumor.
  • the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a statin.
  • the statin comprises atorvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, or combinations thereof, or a combination of a statin and another agent, such as ezetimibe/simvastatin.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with atorvastatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with fluvastatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with lovastatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with mevastatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pitavastatin.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pravastatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with rosuvastatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with simvastatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ezetimibe/simvastatin.
  • the method comprises selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a repurposed drug therapy.
  • a repurposed drug therapy comprises eflornithine, indinavir, metformin, or ritonavir, or any combination thereof.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with eflornithine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with indinavir. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with metformin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ritonavir.
  • the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a small molecule inhibitor therapy.
  • a small molecule inhibitor therapy comprises administration of belinostat, bortezomib, copanlisib, crizotinib, imatinib, dasatinib, dovitinib, rapamycin, everolimus, sirolimus, tipifarnib, pazopanib, alisertib, sapanisertib, lapatinib, lonafarnib, merestinib, olaparib, palbociclib, bosutinib, sorafenib, erlotinib, sunitinib, cabozantinib, gefitinib, ixazomib, vistusertib, vorinostat
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with belinostat. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with bortezomib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with copanlisib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with crizotinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with imatinib.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with dasatinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with dovitinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with rapamycin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with everolimus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with sirolimus.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with tipifarnib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pazopanib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with alisertib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with sapanisertib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with lapatinib.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with lonafarnib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with merestinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with olaparib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with palbociclib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with bosutinib.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with sorafenib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with erlotinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with sunitinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with cabozantinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with gefitinib.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ixazomib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with vistusertib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with vorinostat. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with entinostat. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with vandetanib.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with BAY1 163877. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with MLN8054. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with PLX3397. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with BGJ398.
  • the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a therapeutic antibody therapy.
  • a therapeutic antibody therapy comprises cetuximab, ritixumab, bevacizumab, ranibizumab, trastuzumab, or panitumumab, fragments thereof, or any combinations thereof, which may be present on one or more CAR T cells.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with cetuximab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ritixumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with bevacizumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ranibizumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with trastuzumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with panitumumab.
  • the method includes selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with an immunotherapy.
  • an immunotherapy comprises nivolumab, durvalumab, pembrolizumab, atezolizumab, ipilimumab, tremelimumab, CA-170, NEO-PV- 01, a tumor cell-derived vaccine therapy, or any combination thereof.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with nivolumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with durvalumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pembrolizumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with atezolizumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ipilimumab.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with tremelimumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with CA-170. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with NEO-PV-01. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with a tumor cell-derived vaccine therapy.
  • the method comprises selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a combination of one or more of orteronel, cyproterone acetate, flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, galeterone, abiraterone, finasteride, ethylstilbestrol (DES), megestrol acetate, fosfestrol, estramustine phosphate, leuprolide, triptorelin, goserelin, histrelin, buserelin, abarelix, degarelix, tamoxifen, clomifene, ormeloxifene, toremifene, lasofoxifene, ospemifene, raloxifene, fulvestrant, brilanestrant, a composition comprising a compound of
  • a pharmaceutical composition comprising a compound of Formula (I) as described herein is used in combination with one or more additional therapy as described herein for the use in treating, inhibiting, delaying, or ameliorating progression of bladder cancer, comprising high risk bladder cancer, stage 0a, stage Ois, I, stage II, stage III, or stage IV bladder cancer growth of bladder cancer cells, or for inhibiting or preventing the onset of bladder cancer, or for decreasing the size of a bladder tumor, or for inhibiting the onset of metastasis associated with bladder cancer.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein is used in combination with one or more additional therapy as described herein for the use in increasing the survival rate of a patient suffering from bladder cancer.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein is used in combination with an additional therapy described herein for the use in increasing the survival rate of a patient suffering from bladder cancer.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein is used in combination with an additional therapy described herein for the use in reducing the size of a tumor or further expansion of cancer cells in a patient suffering from bladder cancer, such as stage 0a, stage Ois, stage I, stage II, stage III, or stage IV bladder cancer, or high risk non muscle-invasive bladder cancer.
  • Some alternatives involve methods for inducing remission of bladder cancer, such as stage 0a, stage Ois, stage I, stage II, stage III, or stage IV bladder cancer, or high risk non muscle- invasive bladder cancer, whereby a pharmaceutical composition comprising a compound of Formula (I) disclosed herein is provided before, during, and/or after providing an additional therapy described herein to a subject suffering from bladder cancer.
  • the methods disclosed herein can result in complete remission of bladder cancer, such as stage 0a, stage Ois, stage I, stage II, stage III, or stage IV bladder cancer, or high risk non-muscle invasive bladder cancer.
  • the methods can result in partial remission of bladder cancer, such as stage 0a, stage Ois, stage I, stage II, stage III, or stage IV bladder cancer, or high risk non-muscle invasive bladder cancer.
  • a pharmaceutical composition comprising a compound of Formula (I) as described herein is used in combination with one or more additional therapy as described herein for the use in treating, inhibiting, delaying, or ameliorating progression of prostate cancer, such as stage I, stage II, stage III or stage IV prostate cancer.
  • the prostate cancer can be castration resistant prostate cancer (CRPC), a prostate cancer that has extended beyond the outer condensed fibromuscular band, also known as the capsule, or metastasis stemming from prostate cancer.
  • the prostate cancer is androgen dependent.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof is used in combination with one or more additional therapy described herein for the use in treating, inhibiting, delaying, or ameliorating progression of prostate cancer, such as stage I, stage II, stage III or stage IV prostate cancer growth of prostate cancer cells, or for inhibiting or preventing the onset of androgen-dependent prostate cancer, or for decreasing the size of a prostate tumor, or for inhibiting the onset of metastasis associated with prostate cancer.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof is used in combination with one or more additional therapy described herein for the use in increasing the survival rate of a patient suffering from prostate cancer.
  • Normal serum testosterone ranges between 1000-300 ng/dL.
  • a subject is provided a combination therapy, as described herein, whereby a reduction in the treated subject's serum testosterone level to at least ⁇ 80, ⁇ 70, ⁇ 60, ⁇ 50, ⁇ 40, ⁇ 30, ⁇ 20, or ⁇ 10 ng/dL is obtained.
  • a subject is provided a combination therapy that reduces the subject's serum testosterone level to at least ⁇ 50 ng/dL.
  • a subject is treated with a combination therapy that results in a reduction in the subject's serum testosterone level to at least ⁇ 20 ng/dL.
  • a subject is treated with a combination therapy, as described herein, that reduces the subject's serum testosterone level to at least or any number in between the range of 120- 70, 100-60, 80-40, 70-30, 50-20, 40-10, 30-10, or 20-10 ng/dL.
  • a subject is treated with a combination therapy that produces a reduction in the subject's serum testosterone level to ⁇ 95%, ⁇ 90%, ⁇ 80%, ⁇ 70%, ⁇ 60%, or ⁇ 50% that of a healthy male.
  • a subject is treated with a combination therapy that results in a reduction in the subject's serum testosterone level to the range of at least or any number in between the range of 5-20%, 10-30%, 20-40%, 30-50%, 40-60%, or 50-70% that of a healthy male.
  • a subject is treated with a combination therapy that results in a reduction in the subject's serum testosterone level to the range of at least or any number in between the range of 1-2%, 2-4%, 1-5%, 4-6%, 4-8%, or 5-10% that of a healthy male.
  • Intermittent hormonal therapy is an alternative to continuous hormonal therapy, which may delay progression of hormone-refractory disease (i.e., CRPC).
  • intermittent therapy can be used for a period of 6 months on, followed by a period of 6 months off.
  • one or more hormonal therapy agents is provided for one month on, followed by one month off.
  • one or more therapy agents are provided for three months on, followed by three months off.
  • one or more of the compounds of Formula (I) can be provided before, during and/or after administering one or more hormonal therapy agents, as described above, so as to reduce or inhibit or delay the onset of CRPC.
  • Standard of care for metastatic CRPC may include taxane-based chemotherapies, such as docetaxel therapy.
  • administration of a pharmaceutical composition comprising a compound of Formula (I), alone or in combination with one or more additional therapy as described herein to a subject according to any one of the methods disclosed herein results in survival of the subject for at least 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 24 months, 36 months, or 48 months or within a range defined by any two of the aforementioned times.
  • administration of a pharmaceutical composition comprising a compound of Formula (I) to a subject according to any one of the methods disclosed herein results in survival of the subject for more than 48 months.
  • administration of a pharmaceutical composition comprising a compound of Formula (I) to a subject according to any one of the methods disclosed herein results in survival of the subject for more than 60 months.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein can be administered prior to all additional therapy described herein.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein can be administered prior to at least one additional therapy described herein.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein can be administered concomitantly with one or more additional therapy described herein.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein can be administered subsequent to the administration of at least one additional therapy described herein.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein can be administered subsequent to the administration of all additional therapy described herein.
  • a subject suffering from cancer such as bladder cancer or prostate cancer, is provided surgical orchiectomy or surgical ovariectomy.
  • a pharmaceutical composition including a compound of Formula (I) disclosed herein can be administered after surgical orchiectomy or surgical ovariectomy.
  • a pharmaceutical composition including a compound of Formula (I) disclosed herein can be administered before and after surgical orchiectomy or surgical ovariectomy. VIII. Dosage amounts of a Compound of Formula (I)
  • the pharmaceutical composition comprising a compound of Formula (I) disclosed herein may contain between 0.01 mg and 3000 mg of a compound of Formula (I), preferably between 1 mg and 700 mg, e.g. 5 to 200 mg.
  • a compound of Formula (I) preferably between 1 mg and 700 mg, e.g. 5 to 200 mg.
  • applications of potential products are commenced at higher dosage levels, with dosage being decreased until the desired effect is no longer achieved or adverse side effects disappear.
  • a pharmaceutical composition comprising a compound of Formula (I) contains an amount of a compound of Formula (I) of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, or 1500 mg or an amount that is within a range defined by any two of the aforementioned amounts.
  • a pharmaceutical composition comprising a compound of Formula (I) contains an amount of a compound of Formula (I) of 0.25 mg per kg body weight of the subject, 0.30 mg per kg body weight of the subject, 0.35 mg per kg body weight of the subject, 0.40 mg per kg body weight of the subject, 0.45 mg per kg body weight of the subject, 0.50 mg per kg body weight of the subject, 0.55 mg per kg body weight of the subject, 0.60 mg per kg body weight of the subject, 0.65 mg per kg body weight of the subject, 0.70 mg per kg body weight of the subject, 0.75 mg per kg body weight of the subject, 0.80 mg per kg body weight of the subject, 0.85 mg per kg body weight of the subject, 0.90 mg per kg body weight of the subject, 0.95 mg per kg body weight of the subject, 1.0 mg per kg body weight of the subject, 1.1 mg per kg body weight of the subject, 1.2 mg per kg body weight of the subject, 1.3 mg per kg body weight of the subject, 1.4 mg per kg body weight of the subject
  • the amount of comprising a compound of Formula (I) may vary from or any number in between 10% to 75% by weight of the total pharmaceutical composition. In some embodiments, the amount of comprising a compound of Formula (I) ranges from or any number in between 10-15%, 12-17%, 15-20%, 17-22%, 25%-30%, 27%-32%, 30%-35%, 32%-37%, 35%-40%, 37%-42%, 40%-45%, 42%-47%, 45%-50%, 47%-52%, 50%-55%, 52%-57%, 55%-60%, 67%-72%, or 70%-75% by weight of the total pharmaceutical composition or an amount that is within a range defined by any two of the aforementioned amounts.
  • the amount of comprising a compound of Formula (I) is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%), at least 65%, at least 70%, or at least 75%, of the weight of the total pharmaceutical composition or an amount that is within a range defined by any two of the aforementioned amounts.
  • the dosage may be a single dosage or a series of two or more given in the course of one or more days, as is needed by the subject.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein can be administered one time per day.
  • Multiple doses of a pharmaceutical composition comprising a compound of Formula (I) can be administered to a subject.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein can be administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid), over a period of time ranging from one day to one week, from two weeks to four weeks, from one month to two months, from two months to four months, from four months to six months, from six months to eight months, from eight months to 1 year, from 1 year to 2 years, or from 2 years to 4 years, or more.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein and an additional therapy described herein can be cyclically administered to a patient. Cycling therapy involves the administration of a first active ingredient for a period of time, followed by the administration of a second active ingredient for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more therapies, avoid or reduce the side effects of one or more therapies, and/or improve the efficacy of the therapy.
  • a pharmaceutical composition comprising a compound of Formula (I) disclosed herein and an additional therapy described herein are administered in a cycle of less than 3 weeks, once every two weeks, once every 10 days, or once every week. The number of cycles can be from 1 to 12 cycles, or from 2 to 10 cycles, or from 2 to 8 cycles.
  • the daily dosage regimen for an adult human patient may be the same or different for two active ingredients provided in combination.
  • the active ingredient is a compound of Formula (I).
  • the active ingredient is a therapy agent as described herein.
  • both an active ingredient including a compound of Formula (I) and an active ingredient of an additional therapy agent are administered to a subject.
  • a compound of Formula (I) can be provided at a dose of between 0.01 mg and 3000 mg, while an additional therapy agent can be provided at a dose of between 1 mg and 700 mg.
  • the dosage or each active ingredient can be, independently, a single one or a series of two or more given in the course of one or more days, as is needed by the subject.
  • the active ingredients will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • a pharmaceutical composition including a compound of Formula (I) disclosed herein can be administered one time per day.
  • the additional therapy agent can be administered once a week.
  • human dosages for active ingredients have been established for at least some condition, those same dosages may be used, or dosages that are between 0.1% and 500%>, more preferably between 25% and 250%> of the established human dosage.
  • a suitable human dosage can be inferred from ED50 or IDso values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each active ingredient but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90%> of the time, preferably between 30-90%> and most preferably between 50-90%>. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
  • Active ingredients disclosed herein can be evaluated for efficacy and toxicity using known methods.
  • the toxicology of a particular active ingredient, or of a subset of the active ingredients, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity of particular compounds in an animal model such as mice, rats, rabbits, or monkeys, may be determined using known methods.
  • the efficacy of a particular active ingredient may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.
  • the toxicology of a pharmaceutical composition including a compound of Formula (I) may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity of a pharmaceutical composition including a compound of Formula (I) may be established by determining in vivo toxicity in an animal model, such as mice, rats, rabbits, or monkeys.
  • Bladder cells mouse urothelial carcinoma MB49 cells were derived from a syngeneic mouse model of bladder cancer that has been widely used for more than 35 years (Summerhayes et al. 1979). MB49 cells recapitulate a key feature of bladder cancer: tumors formed in animals using MB49 cells grow significantly better in male mice than female mice (White-Gilbertson et al. Bladder, 2016, 3, ell). Other mouse bladder cancer cells may be used as well. Stable expression of H2B-GFP in mouse cancer cells was achieved as described previously (Abedinpour et al. Prostate, 2013, 73, 489-499; Abedinpour et al. Prostate, 2011, 71, 813-823).
  • a collection of 8 human bladder cancer cell lines with various genetic mutations representative of human cancer were purchased from ATCC (American Type Culture Collection, Manassas, VA). Half of these cell lines have been shown to be positive for AR while at least one of the cell lines has been shown to lack AR.
  • All cell lines were grown in their appropriate culture medium, such as, for example, DMEM containing 2mM L-glutamine, glucose (4.5g/ml), Glutamine, 10% FBS (Fetal Bovine Serum), 100 U/ml penicillin and 100 ⁇ g/ml streptomycin.
  • Human bladder cancer cells (urothelial carcinoma) were grown in high-glucose DMEM (Dulbecco's Modified Eagle's Medium) containing 10% FBS (fetal bovine serum), 2 mM L-glutamine, and 100 U/mL penicillin/100 ⁇ g/mL streptomycin.
  • Geneticin G418 was added to the growth medium of bladder cancer cells transfected with H2B-GFP to maintain expression of the transfected protein.
  • Prostate cells PTEN-P2/GFP are cells that stably express histone H2B- GFP fusion protein. Kanda et al. ⁇ Kanda T, Sullivan KF, Wahl GM. Histone-GFP fiision protein enables sensitive analysis of chromosome dynamics in living mammalian cells. Curr Biol 1998 Mar 26;8(7):377-85). These investigators developed a highly sensitive method for observing chromosome dynamics in living cells. They fused the human Histone H2B gene to the gene encoding the GFP, which was transfected into human HeLa cells to generate a stable line constitutively expressing H2B-GFP.
  • the H2B-GFP fusion protein was incorporated into chromatin without affecting cell cycle progression.
  • cDNA encoding a Histone H2B-GFP fusion protein under the 5'LTR in the LXRN retroviral cassette was generated, and introduced into a number of humans, as well as murine cancer cell lines by retroviral transduction.
  • Cells were grown in phenol red-free DMEM medium containing 10% FBS, 2 mM L-glutamine, 100 U/ml penicillin/100 ⁇ g/ml streptomycin, insulin-selenium- transferrin (5 ⁇ g/ml insulin), and DHT 10 "8 M final. Cells were maintained in a humidified incubator at 37°C and 5% CO2. G418 (100 ⁇ g/ml) was added to maintain stable expression of H2B-GFP.
  • mice All procedures involving mice were approved by the Institutional Animal Care and Use Committee of Explora Biolabs (San Diego, CA) and carried out according to NIH recommended procedures and precautions. All mice were purchased from Jackson laboratory (Bar Harbor, ME). Mice were about 6 to 8 weeks old, and weigh about 20-25 g at the start of the experiments. Mice were housed at a maximum of two per cage, under standard room conditions, with ad libidum food and water. Every effort was made to minimize animal suffering.
  • mice were anesthetized before surgery and received analgesics after surgery according to IACUC-approved procedures. Surgeries were performed in a sterile laminar flow hood with proper instrument sterilization and approved procedures.
  • mice Male Nude mice (25-35 g body weight) were anesthetized (7.3 mg ketamine hydrochloride and 2.3 mg xylazine /100 g body weight, i.p.) and placed on a heating pad. Two symmetrical titanium frames were implanted into a dorsal skinfold, so as to sandwich the extended double layer of skin. A 15 mm full thickness circular layer was excised. The underlying muscle and subcutaneous tissues were covered with a glass coverslip incorporated in one of the frames. After a recovery period of 2-3 days, bladder tissue and cancer cell spheroids were carefully placed in the chamber. Small circular Band Aids were applied on the backside of the chamber after surgery to prevent scratching.
  • Liquid overlay plates were generated using 1% molecular biology grade agarose melted in cell culture medium and plated in round bottom 96 well plates at 50ul/well. Tumor cells grown as pre-confluent monolayers were trypsinized and diluted to a final volume of 1,000,000 cells/ml. Viability was determined by Trypan blue. Cells were placed onto the cooled agarose (70 ⁇ /well) and allowed to compact into spheroids for 24 hours. The spheroids were picked with a pipette and transferred into serum-free media for implantation in the chambers.
  • IVMS Intravital Microscopy
  • Intravital Microscopy can be used to visualize tumors in animals and analyze various aspects of cancer physiology such as tumor vascularization, cell migration and metastasis.
  • An advantage of IVM includes the real-time analysis of dynamic processes with single-cell resolution. IVM offers the possibility to follow tumor growth in a non-invasive, non-destructive manner. The application of IVM can be limited to animal models that bear visually accessible tumors. Therefore, the dorsal skinfold chamber model described above can be compatible with IVM.
  • IVM intracranial pressure regulator
  • Tumor growth experiments in vivo were performed using IVM in a pseudo-orthotopic chamber model as previously described.
  • titanium chambers were placed by surgery in nude mice and syngeneic bladder tissue was grafted into the chamber two days later.
  • Tumor spheroids containing 50,000 to 70,000 H2B-GFP-positive mouse bladder cancer cells were placed on the grafted bladder tissue 7 days later, once the tissue was vascularized.
  • mice Two days later, the mice were castrated or treated with the drug of interest (for example, placebo, androgen deprivation therapy, anti-estrogen therapy, a biologic, a virus-based therapy, surgery, chemotherapy, antineoplastic agent, radiation therapy, statin, repurposed drug therapy, small molecule inhibitor therapy, therapeutic antibody therapy, immunotherapy, or combinations thereof, optionally, wherein the chemotherapy or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy) a day before initiation of the treatment with a compound of Formula (I).
  • the drug of interest for example, placebo, androgen deprivation therapy, anti-estrogen therapy, a biologic, a virus-based therapy, surgery, chemotherapy, antineoplastic agent, radiation therapy, statin, repurposed drug therapy, small molecule inhibitor therapy, therapeutic antibody therapy, immunotherapy, or combinations thereof, optionally, wherein the chemotherapy or
  • Orthotopic tumor inoculation was performed by transducing MB49 mouse bladder tumor cells with a lentiviral construct to stably express the firefly luciferase gene. These cells have been certified free of rodent pathogens. They were cultured in normal growth medium before injection into mice. Experiments looking at the efficacy of ADT on tumor growth were performed using 10 week-old C57/B16 male mice. Other experiments were performed in both female and male mice.
  • mice were contacted with each drug of interest, alone or in combination, according to the drug route of administration and schedule.
  • a compound of Formula (I) can be administered per oral in drinking water or by gavage five days a week.
  • Tumor growth was assessed in real-time by animal imaging using a Caliper Life Sciences IVIS Lumina II Imager that takes advantage of luciferase expression by the tumor cells. Imaging was performed twice a week. If metastasis was visible, the number and size of metastatic tumors was recorded. Mice were killed at the end of the experiment according to IACUC-approved procedure and the tumor was resected. A portion of the tumor tissue was fixed in formaldehyde for IHC (immunohistochemistry) staining and another portion of tumor tissue was flash-frozen for gene expression and protein analysis. Survival studies
  • a well-established carcinogen-induced bladder cancer model was used. Mice were administered, for example, 0.05% BBN (N-butyl-N-(4-hydroxybutyl) nitrosamine) in their drinking water continuously for eight weeks, which induces the formation of tumors in the bladder. After 8 weeks of BBN exposure, animals resumed drinking water without BBN.
  • BBN N-butyl-N-(4-hydroxybutyl) nitrosamine
  • mice were then surgically castrated or started on androgen deprivation therapy, anti-estrogen therapy, a biologic, a virus-based therapy, surgery, chemotherapy, antineoplastic agent, radiation therapy, statin, repurposed drug therapy, small molecule inhibitor therapy, therapeutic antibody therapy, immunotherapy, or combinations thereof, optionally, wherein the chemotherapy or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
  • Treatment with a compound of Formula (I) was initiated 2-4 days later. The number of days mice lived following treatment initiation was recorded for each animal.
  • mice were euthanized by a technician blinded to the study when they lost more than 15% of their weight or showed signs of pain though posture and lack of grooming, whichever came first, in agreement with our IACUC regulations. Once euthanized, the mice were necropsied for tissue harvesting and examination. The tumor was excised, and halt of the tumor tissue was flash-frozen while the other half was immerged in para-formaldehyde for immuno-histology.
  • compositions including a compound of Formula (I) were administered by oral gavage.
  • the composition was prepared by dissolving a compound of Formula (I) in DMSO then in oil at a concentration of 0.25 mg/mL (weight/volume) with a final DMSO concentration of 0.5% (vol/vol), and administered to mice at a dose of 1 mg/kg.
  • Prostate cancer cells were grown in their appropriate culture medium as described previously. Briefly, cells were plated in 12-well plates in normal growth medium. One or two days after plating, cells were contacted with increasing concentrations of a compound of Formula (I) for a period of 24 hours. Cell proliferation was determined by counting the cells using a Cell Coulter instrument (Beckman). As shown in Figures 3A-3B, contact with a compound of Formula (I) caused a sharp decrease in cell numbers within a narrow range of concentrations in human LNCaP prostate cancer cells ( Figure 3A), human DU145 prostate cancer cells (Figure 3B), and in human PC3 prostate cancer cells ( Figure 3C).
  • the graphs represent residual cell viability expressed as a percent of control and are means ⁇ SEM of at least 4 separate experiments, each performed in duplicate. Similar EC50 across cell lines was observed between about 2 and 3 ⁇ . No significant difference was observed between cell lines, irrespective of their androgen sensitivity (androgen-dependent LNCaP or androgen-independent PC3 and DU145).
  • mouse cell lines were also contacted with a compound of Formula (I).
  • Cells were plated in 96-well plates in normal growth medium. The day after plating, cells were contacted with increasing concentrations of a compound of Formula (I) for a period of 24 hours. Cell viability was determined using the WST1 reagent.
  • the compound of Formula (I) decreased cell viability in mouse prostate cell PTEN-P2 ( Figure 4A) and PTEN-CAP2 ( Figure 4B).
  • ⁇ - P2 and PTEN-CAP2 are two mouse isogenic cell lines that differ only by the presence or absence of the PTEN gene. Hence, PTEN-P2 express PTEN; whereas PTEN-CAP2 do not.
  • the compound of Formula ( I ) has a similar effect in both cell lines, with an EC50 between 2 and 3 ⁇ (similar to human prostate cancer cells). Results are expressed as percent of control and are means ⁇ SEM of at least 5 independent experiments, each performed in triplicates. Figure 4C directly compares the effect of Formula (I) in the two cell lines to show the similarity of the dose-response.
  • docetaxel decreased the viability of prostate cancer cells to a limited extent.
  • the effect of docetaxel after 24 hours of contact reached a plateau at a concentration of 0.1 ⁇ and killed a maximum of 20% human prostate cancer cells DU145.
  • the maximum effect of docetaxel differed between cell lines, killing about 40% of human PC3 cells and in mouse PTEN-P2 cells, with an EC50 in the range of 0.01 ⁇ in most cell lines.
  • Bladder cancer cells were grown in their appropriate culture medium, such as, for example, DMEM containing 2mM L-glutamine, glucose (4.5g/ml), Glutamine, 10% FBS (Fetal Bovine Serum), 100 U/ml penicillin and 100 ⁇ g/ml streptomycin.
  • DMEM fetal calf serum
  • FBS Fetal Bovine Serum
  • compositions including a compound of Formula (I) were measured by Western blot (protein levels) and qRT-PCR (mRNA levels) according to standard procedures.
  • Compositions including a compound of Formula (I) may decrease AR levels, and also may decrease ER levels in ER-positive cells.
  • compositions including a compound of Formula (I) were assessed by contacting the cells with increasing concentrations of a compound of Formula (I) for 24 hours up to several days followed by the WST-1 assay.
  • the dose corresponding to the ICso of a compound of Formula (I) was used in combination with increasing doses of an additional therapy, including androgen deprivation therapy, anti-estrogen therapy, a biologic, a virus-based therapy, surgery, chemotherapy (including taxane-based chemotherapy agents), antineoplastic agent (including platinum-based antineoplastic agents), radiation therapy, statin, repurposed drug therapy, small molecule inhibitor therapy, therapeutic antibody therapy, immunotherapy, or combinations thereof, optionally, wherein the chemotherapy or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy to measure cell proliferation/viability using the WST-1 assay.
  • an additional therapy including androgen deprivation therapy, anti-estrogen therapy, a biologic, a virus-based therapy, surgery, chemotherapy (including taxane-based chemotherapy agents), antineoplastic agent (including platinum-based antineo
  • Mouse bladder cancer cells were plated in 96-well plate the day before treatment. A composition including a compound of Formula (I) was added at increasing concentrations using serial dilutions from a stock solution. The control condition consisted of DMSO alone. Cells were incubated with a composition including a compound of Formula (I) for 24 hours at 37°C and 5% CO2 in normal cell growth conditions. As shown in Figures 7A-7C, the compound of Formula (I) decreased the viability of bladder cancer cells with an EC50 between 3 to 4 ⁇ , and achieved complete toxicity at 6 ⁇ , including in MB49 cells (Figure 7A), CRL1749 cells ( Figure 7B), and HTB5 cells ( Figure 7C). Results are expressed as percent of control and are means ⁇ SEM of several independent experiments, each performed in triplicates.
  • Cancer cells including mouse MB49 cells or human CRL1749 bladder cancer cells, were plated in a 96-well plate the day before treatment and maintained in normal growth medium.
  • Cell viability was assessed using WST-1 reagent.
  • FIG. 8A As shown in Figure 8A, valrubicin decreased the viability of prostate cancer cells to a maximum effect of 20% remaining viable cells (80% cells killed), reached at a concentration of 40 ⁇ . ECso was in the range of 10 ⁇ . Results are expressed as percent of control and are means ⁇ SEM of 2 independent experiments, each performed in triplicates.
  • Figure 8B depicts the results of cisplatin alone in MB49 cells.
  • Figure 8C depicts the results of cisplatin in CRL1749 cells.
  • a test experiment was performed to assess the combination effect of valrubicin and a compound of Formula (I) ( Figure 10).
  • the compound of Formula (I) was used in an amount of 2 ⁇ , and was effective, killing 80% of the cells when used alone.
  • the mouse chamber model was used to assess the efficacy of a compound of Formula (I) alone or in combination in a clinically relevant model.
  • mice are separated into several treatment groups: i) untreated (or sham- treated); ii) a compound of Formula (I) alone; iii) androgen deprivation therapy, anti- estrogen therapy, a biologic, a virus-based therapy, surgery, chemotherapy (including taxane- based chemotherapy agents), antineoplastic agent (including platinum-based antineoplastic agents), radiation therapy, statin, repurposed drug therapy, small molecule inhibitor therapy, therapeutic antibody therapy, immunotherapy, or combinations thereof, optionally, wherein the chemotherapy or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy; and iv) combinations of a compound of Formula (I) with either modality or drug used in iii).
  • Tumor growth is measured by IVM as a function of time for several weeks as described in previous studies (Abedinpour et al. Prostate, 2013, 73, 489-499; Abedinpour et al. Prostate, 2011, 71, 813-823). Within subjects continuous variables are compared between groups using repeated measures ANOVA.

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Abstract

Disclosed herein pharmaceutical compositions that include a compound of Formula (I) in combination with a cancer therapy treatment, such as a taxane-based chemotherapeutic or a platinum-based antineoplastic agent and methods of treating and/or ameliorating diseases and/or conditions associated with a cancer, such as bladder cancer or prostate cancer with such combinations of a compound of Formula (I) and a cancer therapy treatment.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF CANCER
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S. Provisional Application Nos. 62/488,230, filed April 21, 2017, and 62/538,964, filed July 31, 2017, the disclosures of which are hereby expressly incorporated by reference in their entirety.
FIELD
[0002] The present disclosure relates to methods and compositions for treating, inhibiting, or ameliorating diseases and/or conditions associated with a cancer, such as prostate cancer or bladder cancer. Specifically, the present disclosure relates to pharmaceutical compositions including naphthoquinone analogs and methods of using these compounds alone or in combination with additional compounds, including androgen deprivation agents, taxane-based chemotherapy agents, and/or platinum-based antineoplastic agents, for treating, ameliorating, or inhibiting a disease and/or condition associated with a cancer, such as prostate cancer or bladder cancer. The disclosure also relates to combination therapeutics and therapies, including naphthoquinone analogs provided in combination with an androgen deprivation agents, taxane-based chemotherapy agents, and/or platinum-based antineoplastic agents, for treating, ameliorating, or inhibiting a disease and/or condition associated with a cancer, such as prostate cancer or bladder cancer, with said combination therapeutic and therapies.
BACKGROUND
[0003] The androgen receptor ("AR") is a ligand-activated transcriptional regulatory protein that mediates induction of a variety of biological effects through its interaction with endogenous androgens. Endogenous androgens include steroids such as testosterone and dihydrotestosterone. Testosterone is converted to dihydrotestosterone by the enzyme 5 alpha-reductase in many tissues.
[0004] The actions of androgens with androgen receptors have been implicated in a number of diseases or conditions, such as androgen dependent cancers, virilization in women, and acne, among others. Compounds that diminish the effects of androgen signaling via the androgen receptor and/or lower the concentrations of androgen receptors find use in the treatment of diseases or conditions in which androgen receptors play a role.
[0005] It is estimated that bladder cancer accounted for 74,000 new cases and 16,000 deaths in the USA in 2015, and 165,000 deaths worldwide. Antoni et al. Eur Urol, 2017, 71, 96-108. Overall, at least 90% of bladder cancer cases are urothelial cell carcinomas which are malignancies of the specialized transitional epithelium lining the organ. Urothelial cell carcinomas of the bladder (UCCB) are classified into two categories termed non-muscle invasive bladder cancer and muscle invasive bladder cancer. Non-muscle invasive bladder cancer is highly treatable, usually by complete resection of the tumor followed by immunotherapy with intra-vesical BCG vaccine or intra-vesical chemotherapy. However, a high proportion of treated patients experience recurrence followed by metastasis. Carneiro et al., Cancer Treat Rev, 2015, 41, 170-178. Muscle invasive disease, although less prevalent (25% to 30%) of bladder cancer patients), is more aggressive with a much higher rate of metastasis.
[0006] The prevalence of bladder cancer in the United States exceeds 500,000 people. While the five-year survival rate for early-stage bladder cancer is high, over 25%> of patients present with advanced disease and around 70%> experience recurrence or progression following treatment. The prognosis for patients with progressive or recurrent invasive bladder cancer is generally poor. Management of recurrent cancers depends on the prior therapy used, site of recurrence, and patient-specific considerations.
[0007] Advanced bladder cancer is difficult to treat and up to 50%> of patients receiving drugs infused into the bladder (intravesical agents) will experience recurrence of the cancer. Advanced metastatic disease is usually treated by radical cystectomy together with neoadjuvant chemotherapy: methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or gemcitabine and cisplatin (GC). Kim, Curr Urol Rep, 2012, 13, 147-152. Unfortunately most patients develop resistance to therapy after an average response duration of about 7 months. Metastatic cancer, although treated aggressively, has dismal survival rates with a median survival time of 15 months (9 months for refractory patients) and a 5-year survival rate of 15% (Oing et al. J Urol, 2016, 195, 254-263).
[0008] Typical second-line treatment for patients with high grade, non-muscle- invasive bladder cancer who have failed standard intravesical therapy is surgical removal of the entire bladder, cystectomy. However many patients are poor surgical candidates or refuse this option.
[0009] Prostate cancer develops in the prostate and is typically slow growing; however, some prostate cancers are aggressive. Prostate cancer cells are typically androgen/testosterone/DHT dependent and may metastasize from the prostate to other parts of the body, particularly the bones and lymph nodes. Treatment options for prostate cancer that remains within the prostate include watchful waiting/active surveillance, external beam radiation therapy, brachytherapy, cryosurgery, high-intensity focused ultrasound (HIFU), and surgery. Hormonal therapy and chemotherapy are often reserved for disease that has spread beyond the prostate. However, there are exceptions in that radiation therapy may be used for some advanced tumors, and hormonal therapy may be used for some early stage tumors.
[0010] After one to three years of hormonal therapy, it is common that prostate cancer cells resume growth despite the androgen/testosterone/DHT blockade. Previously referred to as "hormone-refractory prostate cancer" or "androgen-independent prostate cancer," the term castration-resistant prostate cancer (CRPC) is now commonly used. Chemotherapeutic agents and immunotherapy have been shown to prolong survival after CRPC but the survival benefit is limited. Despite the efforts of many, the need for more cancer treatments, in particular bladder cancer and prostate cancer treatments, is manifest.
SUMMARY
[0011] It is therefore an aspect of this disclosure to provide pharmaceutical compositions and methods of use thereof for the treatment, amelioration, or inhibition of cancer, such as bladder cancer or prostate cancer.
[0012] Some embodiments provided herein relate to a product combination for the inhibition or treatment of prostate cancer. In some embodiments, the product combination comprises: a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000005_0001
[0013] In some embodiments, R1 is methyl; R2 is hydrogen; R3 is -OH; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen. In some embodiments, the product combination further comprises a therapeutically effective amount of a taxane-based chemotherapy agent.
[0014] In some embodiments, the taxane-based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof. In some embodiments, the compound of Formula (I) is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts. In some embodiments, the taxane-based chemotherapy agent is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts. In some embodiments, said product combination inhibits the growth of prostate cancer. In some embodiments, said product combination inhibits or delays the onset of castration-resistant prostate cancer. In some embodiments, the compound of Formula (I) is formulated for oral or parenteral administration. In some embodiments, the taxane-based chemotherapy agent is formulated for oral or parenteral administration. In some embodiments, the compound of Formula (I) and the taxane-based chemotherapy agent are provided to a subject in a single formulation or a single dosage. In some embodiments, the compound of Formula (I) and the taxane-based chemotherapy agent are formulated for oral or parenteral administration. In some embodiments, said prostate cancer is androgen dependent prostate cancer. In some embodiments, said prostate cancer is castration-resistant prostate cancer. In some embodiments, the product combination reduces prostate cancer tumor size. [0015] Some embodiments provided herein relate to a method of inhibiting or treating prostate cancer. In some embodiments, the method comprises administering to a subject having prostate cancer a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000006_0001
[0016] In some embodiments, R1 is methyl; R2 is hydrogen; R3 is -OH; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen. In some embodiments, the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a taxane-based chemotherapy agent. In some embodiments, the prostate cancer is inhibited or treated.
[0017] In some embodiments, said method inhibits the growth of prostate cancer. In some embodiments, said method inhibits or delays the onset of castration-resistant prostate cancer. In some embodiments, the taxane-based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof. In some embodiments, the compound of Formula (I) is administered to the subject orally or parenterally. In some embodiments, the taxane-based chemotherapy agent is administered to the subject orally or parenterally. In some embodiments, the compound of Formula (I) and the taxane-based chemotherapy agent are administered to the subject orally or parenterally. In some embodiments, said prostate cancer is androgen dependent prostate cancer. In some embodiments, said prostate cancer is castration-resistant prostate cancer. In some embodiments, prostate cancer tumor size is reduced.
[0018] Some embodiments provided herein relate to a product combination for the inhibition or treatment of prostate cancer. In some embodiments, the product combination comprises: a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000007_0001
[0019] In some embodiments, R1 is methyl; R2 is hydrogen; R3 is -OH; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen. In some embodiments, the product combination further comprises a therapeutically effective amount of a platinum-based antineoplastic agent.
[0020] In some embodiments, the platinum-based antineoplastic agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, or satraplatin, or analogues or derivatives thereof. In some embodiments, the compound of Formula (I) is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts and wherein the platinum-based antineoplastic agent is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts. In some embodiments, said product combination inhibits the growth of prostate cancer. In some embodiments, said product combination inhibits or delays the onset of castration-resistant prostate cancer. In some embodiments, the compound of Formula (I) is formulated for oral or parenteral administration. In some embodiments, the platinum-based antineoplastic agent is formulated for oral or parenteral administration. In some embodiments, the compound of Formula (I) and the platinum -based antineoplastic agent are provided to a subject in a single formulation or a single dosage. In some embodiments, the compound of Formula (I) and the platinum-based antineoplastic agent are formulated for oral or parenteral administration. In some embodiments, said prostate cancer is androgen dependent prostate cancer. In some embodiments, said prostate cancer is castration-resistant prostate cancer. In some embodiments, the product combination reduces prostate cancer tumor size.
[0021] Some embodiments provided herein relate to a method of inhibiting or treating prostate cancer. In some embodiments, the method comprises administering to a subject having prostate cancer a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000008_0001
[0022] In some embodiments, R1 is methyl; R2 is hydrogen; R3 is -OH; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen. In some embodiments, the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a platinum-based antineoplastic agent. In some embodiments, the prostate cancer is inhibited or treated.
[0023] In some embodiments, said method inhibits the growth of prostate cancer. In some embodiments, said method inhibits or delays the onset of castration-resistant prostate cancer. In some embodiments, the platinum-based antineoplastic agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, or satraplatin, or analogues or derivatives thereof. In some embodiments, the compound of Formula (I) is administered to the subject orally or parenterally. In some embodiments, the platinum-based antineoplastic agent is administered to the subject orally or parenterally. In some embodiments, the compound of Formula (I) and the platinum-based antineoplastic agent are administered to the subject orally or parenterally. In some embodiments, said prostate cancer is androgen dependent prostate cancer. In some embodiments, said prostate cancer is castration-resistant prostate cancer. In some embodiments, the prostate cancer tumor size is reduced.
[0024] Some embodiments provided herein relate to a product combination that inhibits or delays the growth of bladder cancer. In some embodiments, the product combination comprises: a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000009_0001
[0025] In some embodiments, R1 is methyl; R2 is hydrogen; R3 is -OH; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen. In some embodiments, the product combination further comprises a therapeutically effective amount of a taxane-based chemotherapy agent.
[0026] In some embodiments, the taxane-based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof. In some embodiments, the compound of Formula (I) is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts, and wherein the taxane-based chemotherapy agent is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts. In some embodiments, said product combination inhibits the growth of bladder cancer. In some embodiments, the compound of Formula (I) is formulated for oral or parenteral administration. In some embodiments, the taxane-based chemotherapy agent is formulated for oral or parenteral administration. In some embodiments, the compound of Formula (I) and the taxane-based chemotherapy agent are provided to a subject in a single formulation or a single dosage. In some embodiments, the compound of Formula (I) and the taxane-based chemotherapy agent are formulated for oral or parenteral administration. In some embodiments, the product combination reduces bladder cancer tumor size.
[0027] Some embodiments provided herein relate to a method of inhibiting or delaying the growth of bladder cancer in a subject. In some embodiments, the method comprises administering to a subject having bladder cancer a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000010_0001
[0028] In some embodiments, R1 is methyl; R2 is hydrogen; R3 is -OH; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen. In some embodiments, the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a taxane-based chemotherapy agent. In some embodiments, the bladder cancer is inhibited or treated.
[0029] In some embodiments, the bladder cancer comprises transitional cell carcinoma, squamous cell carcinoma, and/or adenocarcinomas of the bladder. In some embodiments, said method inhibits the growth of bladder cancer. In some embodiments, said method inhibits or delays the onset of bladder cancer. In some embodiments, the taxane- based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof. In some embodiments, the compound of Formula (I) is administered to the subject orally or parenterally. In some embodiments, the taxane-based chemotherapy agent is administered to the subject orally or parenterally. In some embodiments, the compound of Formula (I) and the taxane-based chemotherapy agent are administered to the subject orally or parenterally. In some embodiments, the bladder cancer tumor size is reduced.
[0030] Some embodiments provided herein relate to a product combination for the inhibition or treatment of bladder cancer. In some embodiments, the product combination comprises: a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000011_0001
[0031] In some embodiments, R1 is methyl; R2 is hydrogen; R3 is -OH; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen. In some embodiments, the product combination further comprises a therapeutically effective amount of a platinum-based antineoplastic agent.
[0032] In some embodiments, the platinum-based antineoplastic agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, or satraplatin, or analogues or derivatives thereof. In some embodiments, the compound of Formula (I) is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts and wherein the platinum-based antineoplastic agent is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts. In some embodiments, said product combination inhibits the growth of bladder cancer. In some embodiments, the compound of Formula (I) is formulated for oral or parenteral administration. In some embodiments, the platinum-based antineoplastic agent is formulated for oral or parenteral administration. In some embodiments, the compound of Formula (I) and the platinum-based antineoplastic agent are provided to a subject in a single formulation or a single dosage. In some embodiments, the compound of Formula (I) and the platinum- based antineoplastic agent are formulated for oral or parenteral administration. In some embodiments, the product combination reduces bladder cancer tumor size.
[0033] Some embodiments provided herein relate to a method of inhibiting or delaying the growth of bladder cancer in a subject. In some embodiments, the method comprises administering to a subject having bladder cancer a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000012_0001
[0034] In some embodiments, R1 is methyl; R2 is hydrogen; R3 is -OH; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen. In some embodiments, the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a platinum-based antineoplastic agent. In some embodiments, the bladder cancer is inhibited or treated.
[0035] In some embodiments, the bladder cancer comprises transitional cell carcinoma, squamous cell carcinoma, and/or adenocarcinomas of the bladder. In some embodiments, said method inhibits the growth of bladder cancer. In some embodiments, said method inhibits or delays the onset of bladder cancer. In some embodiments, the platinum- based antineoplastic agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, or satraplatin, or analogues or derivatives thereof. In some embodiments, the compound of Formula (I) is administered to the subject orally or parenterally. In some embodiments, the platinum-based antineoplastic agent is administered to the subject orally or parenterally. In some embodiments, the compound of Formula (I) and the platinum-based antineoplastic agent are administered to the subject orally or parenterally. In some embodiments, the bladder cancer tumor size is reduced.
[0036] Some embodiments provided herein relate to a product combination and methods of use thereof for the inhibition of or the delayed growth or progression of bladder cancer. In some embodiments, the product combination, which can be used in such methods, comprises a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000013_0001
[0037] In some embodiments, R1 is methyl, R2 is hydrogen, R3 is -OH, R4 is hydrogen, R5 is hydrogen, and R6 is hydrogen. In some embodiments, the product combination and methods of use thereof further comprises a therapeutically effective amount of a hormone deprivation agent. In some embodiments, the hormone deprivation agent is an anti-testosterone or androgen deprivation agent or an anti-estrogen or estrogen deprivation agent. In some embodiments, the androgen deprivation agent is orteronel, cyproterone acetate, flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, galeterone, abiraterone, finasteride, ethyl stilbestrol (DES), megestrol acetate, fosfestrol, estramustine phosphate, leuprolide, triptorelin, goserelin, histrelin, buserelin, abarelix, degarelix, or derivatives, salts, or analogues thereof, or combinations thereof. In some embodiments, the anti-estrogen agent is tamoxifen, clomifene, ormeloxifene, toremifene, lasofoxifene, ospemifene, raloxifene, fulvestrant, brilanestrant, elacestrant, anastrozole, letrozole, testolactone, exemestane, or derivatives, salts, or analogues thereof, or combinations thereof. In some embodiments, the estrogen deprivation agent is tamoxifen, clomifene, ormeloxifene, toremifene, lasofoxifene, ospemifene, raloxifene, fulvestrant, brilanestrant, elacestrant, anastrozole, letrozole, testolactone, exemestane, or derivatives, salts, or analogues thereof, or combinations thereof. In some embodiments, the compound of Formula (I) is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts, and wherein the hormone deprivation agent is present in an amount of 0.1 μΜ ΐο 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts. In some embodiments, the product combination and accompanying methods inhibit the growth and/or progression of bladder cancer. In some embodiments, the compound of Formula (I) is formulated for oral or parenteral administration. In some embodiments, the hormone deprivation agent is formulated for oral or parenteral administration. In some embodiments, the compound of Formula (I) and the hormone deprivation agent are provided to a subject in a single formulation or a single dosage. In some embodiments, the compound of Formula (I) and the hormone deprivation agent are formulated for separate administration. In some embodiments, the product combination and accompanying method reduces bladder cancer tumor size.
[0038] Some embodiments provided herein relate to a method of inhibiting or delaying the growth of bladder cancer in a subject. In some embodiments, the method includes administering to a subject having bladder cancer, such as a subject identified or selected as one having bladder cancer, a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
-3 0 (I)
[0039] In some embodiments R1 is methyl, R2 is hydrogen, R3 is -OH, R4 is hydrogen, R5 is hydrogen, and R6 is hydrogen. In some embodiments, the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a hormone deprivation agent, such as an androgen deprivation or estrogen deprivation agent. In some embodiments, the bladder cancer is inhibited or treated. In some embodiments, the bladder cancer comprises transitional cell carcinoma, squamous cell carcinoma, and/or adenocarcinomas of the bladder. In some embodiments, the method inhibits the growth of bladder cancer. In some embodiments, the method inhibits or delays the onset or progression of bladder cancer. In some embodiments, the hormone deprivation agent is an androgen deprivation agent or an anti-testosterone agent or an estrogen deprivation agent or an anti-estrogen agent. In some embodiments, the androgen deprivation agent is orteronel, cyproterone acetate, flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, galeterone, abiraterone, finasteride, ethylstilbestrol (DES), megestrol acetate, fosfestrol, estramustine phosphate, leuprolide, triptorelin, goserelin, histrelin, buserelin, abarelix, degarelix, or derivatives, salts, or analogues thereof, or combinations thereof. In some embodiments, the anti-estrogen agent is tamoxifen, clomifene, ormeloxifene, toremifene, lasofoxifene, ospemifene, raloxifene, fulvestrant, brilanestrant, elacestrant, anastrozole, letrozole, testolactone, exemestane, or derivatives, salts, or analogues thereof, or combinations thereof. In some embodiments, the compound of Formula (I) is administered to the subject orally or parenterally. In some embodiments, the hormone deprivation agent is administered to the subject orally or parenterally. In some embodiments, the compound of Formula (I) and the hormone deprivation agent are administered to the subject orally or parenterally, which can be in separate administrations. In some embodiments, bladder cancer tumor size is reduced. [0040] Some embodiments provided herein relate to a product combination for the inhibition or treatment of cancer. In some embodiments, the product combination includes a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000016_0001
[0041] In some embodiments, R1 is methyl, R2 is hydrogen, R3 is -OH, R4 is hydrogen, R5 is hydrogen, and R6 is hydrogen. In some embodiments, the product combination further includes a therapeutically effective amount of a chemotherapy agent, optionally, wherein the chemotherapy agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
[0042] In some embodiments, the chemotherapy agent is 5-fluorouracil, doxorubicin, gemcitabine, methotrexate, mitomycin C, valrubicin, or vinblastine, or analogues, derivatives, or combinations thereof. In some embodiments, the chemotherapy agent is an antineoplastic agent or a taxane-based chemotherapy agent. In some embodiments, the antineoplastic agent in a platinum-based antineoplastic agent selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, and satraplatin, or analogues or derivatives thereof. In some embodiments, the taxane-based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof. In some embodiments, the compound of Formula (I) is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts and wherein the chemotherapy agent is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts. In some embodiments, the cancer is prostate cancer or bladder cancer. In some embodiments, the product combination inhibits the growth of bladder cancer or inhibits the growth of prostate cancer. In some embodiments, the compound of Formula (I) is formulated for oral or parenteral administration. In some embodiments, the chemotherapy agent is formulated for oral or parenteral administration. In some embodiments, the compound of Formula (I) and the chemotherapy agent are provided to a subject in a single formulation or a single dosage. In some embodiments, the compound of Formula (I) and the chemotherapy agent are formulated for oral or parenteral administration. In some embodiments, the product combination reduces bladder cancer tumor size or reduces prostate cancer tumor size.
[0043] Some embodiments provided herein relate to a method of inhibiting or delaying the growth of cancer in a subject. In some embodiments, the method includes administering to a subject having cancer a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000017_0001
[0044] In some embodiments, R1 is methyl, R2 is hydrogen, R3 is -OH, R4 is hydrogen, R5 is hydrogen, R6 is hydrogen. In some embodiments, the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a chemotherapy agent, optionally, wherein the chemotherapy agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy; and wherein the cancer is inhibited or treated. In some embodiments, the chemotherapy agent is 5-fluorouracil, doxorubicin, gemcitabine, methotrexate, mitomycin C, valrubicin, or vinblastine, or analogues, derivatives, or combinations thereof. In some embodiments, the chemotherapy agent is an antineoplastic agent or a taxane-based chemotherapy agent. In some embodiments, the antineoplastic agent in a platinum-based antineoplastic agent selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, and satraplatin, or analogues or derivatives thereof. In some embodiments, the taxane-based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof. In some embodiments, the cancer is bladder cancer or prostate cancer. In some embodiments, the bladder cancer comprises transitional cell carcinoma, squamous cell carcinoma, and/or adenocarcinomas of the bladder. In some embodiments, the method inhibits the growth of bladder cancer or inhibits the growth or prostate cancer. In some embodiments, the method inhibits or delays the onset of bladder cancer or inhibits or delays the onset of prostate cancer. In some embodiments, the compound of Formula (I) is administered to the subject orally or parenterally. In some embodiments, the chemotherapy agent is administered to the subject orally or parenterally. In some embodiments, the compound of Formula (I) and the chemotherapy agent are administered to the subject orally or parenterally. In some embodiments, a size of a bladder cancer tumor or a size of a prostate cancer tumor is reduced.
BRIEF DESCRIPTION OF THE DRAWINGS
[0045] Figure 1 illustrates the effect of a compound of Formula (I) on androgen receptor (AR) protein levels. Mouse cancer cells PTEN-P2 (left panel) and human cancer cells LNCap (right panel), which express the androgen receptor and are grown in the presence of dihydrotestosterone (DHT) at 10"8 M, were incubated with increasing concentrations of a compound of Formula (I) ranging from 1 to 8 μΜ for 24 hours. Cells were lysed and AR protein levels were analyzed by Western blot. Membranes were stripped and re-probed for actin following standard procedures. Results show that compound of Formula (I) decreases AR protein in human and mouse cancer cells. [0046] Figure 2 illustrates Western blot results of androgen receptor protein levels. TRAMP-C2 mouse prostate cancer cells (left panel) were grown in phenol red-free medium and treated with or without DHT (10"8 M) for 24 hours. Cells were then treated with or without a compound of Formula (I) (8 μΜ) for 6 hours. Cells were lysed and AR protein levels were analyzed by western blot. Membranes were reprobed with anti-actin antibodies. PTEN-P2 mouse prostate cancer cells (right panel) were grown in phenol red-free medium in the presence of DHT (10"8 M) for 24 hours. Cells were treated with a compound of Formula (I) (8 μΜ) for 0, 2, or 6 hours or with DMSO for hours (Ctl). Cells were lysed and AR protein levels were analyzed by western blot. Membranes were stripped and reprobed with anti-actin antibodies.
[0047] Figures 3A-3C illustrate the toxicity of a compound of Formula (I) in prostate cancer cell lines, including LNCaP cells (Figure 3A), DU145 cells (Figure 3B), and PC3 cells (Figure 3C).
[0048] Figures 4A-4C illustrate the toxicity of a compound of Formula (I) in mouse prostate cancer cells, including in PTEN-P2 cells (Figure 4 A) and PTEN-CAP2 cells (Figure 4B). Figure 4C directly compared the effect of the compound of Formula (I) in the two cell lines, and depicts a similarity in the dose response.
[0049] Figures 5A-5D illustrate the toxicity of docetaxel in various cell lines, including DU145 cells (Figure 5A), PC3 cells (Figure 5B), PTEN-P2 cells (Figure 5C), and PTEN-CAP2 cells (Figure 5D).
[0050] Figures 6A and 6B illustrate cell viability of PC3 cells (Figure 6A) and PTEN-P2 cells (Figure 6B) in the presence of docetaxel alone or in combination with a compound of Formula (I).
[0051] Figures 7A-7C illustrate the cytotoxicity of a compound of Formula (I) in bladder cancer cell lines, including mouse MB49 cells (Figure 7A), human CRL1749 cells (Figure 7B), and human HTB5 cells (Figure 7C).
[0052] Figures 8A-8C illustrate the cytotoxicity of valrubicin in mouse MB49 bladder cancer cells (Figure 8A), of cisplatin in mouse MB49 bladder cancer cells (Figure 8B), and of cisplatin in human CRL1749 bladder cancer cells (Figure 8C). [0053] Figure 9 illustrates treatment of cancer cells using cisplatin, a compound of Formula (I), or a combination of cisplatin and a compound of Formula (I) in human CRL1749 bladder cancer cells.
[0054] Figure 10 illustrates cell viability of mouse MB49 bladder cancer cells in the presence of valrubicin alone or in combination with a compound of Formula (I).
DETAILED DESCRIPTION
[0055] Embodiments provided herein relate to methods and compositions to treat, ameliorate, inhibit, prevent, or delay cancer cell growth or cancer in a subject, such as bladder cancer or prostate cancer. The methods of inhibiting or delaying the growth of cancer, including bladder cancer or prostate cancer, comprise administering to a subject or patient having a cancer such as a bladder cancer or a prostate cancer (e.g., a subject identified or selected as being one in need of an agent that treats or inhibits a cancer, such as prostate cancer or bladder cancer), a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I), alone or in combination with an androgen deprivation agent or therapy, an anti-estrogen agent or therapy, a biological agent or therapy, a virus-based agent or therapy, surgery, a chemotherapeutic agent or chemotherapy, such as a taxane-based chemotherapy agent, an antineoplastic agent, such as a platinum-based antineoplastic agent, radiation or radiation therapy, a statin or a statin therapy, a repurposed drug or a repurposed drug therapy, a small molecule inhibitor or a small molecule inhibitor therapy, a therapeutic antibody or a therapeutic antibody therapy, a CAR T cell or a CAR T cell therapy, an immunotherapeutic agent or an immunotherapy, or any combination thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy. Also provided are compositions that comprise a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I) in combination with an androgen deprivation agent, an anti-estrogen agent, a biological agent, a virus-based agent, a chemotherapeutic agent, such as a taxane-based chemotherapy agent, an antineoplastic agent, such as a platinum-based antineoplastic agent, a statin, a repurposed drug, a small molecule inhibitor, a therapeutic antibody, a CAR T cell, an immunotherapeutic agent, or any combination thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy.
I. Definitions
[0056] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are expressly incorporated by reference in their entireties unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
[0057] As used herein, any "R" group(s) such as, without limitation, R, R1, R2, R3, R4, R5, R6 R7, R8, R9, R10, R11, R12, R13, and R14 represent substituents that can be attached to the indicated atom. An R group may be substituted or unsubstituted.
[0058] As used herein, "Ca to Cb" in which "a" and "b" are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the cycloalkynyl, ring of the aryl, ring of the heteroaryl or ring of the heteroalicyclyl can contain from "a" to "b", inclusive, carbon atoms. Thus, for example, a "Ci to C4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and/or (CH3)3C-. If no "a" and "b" are designated with regard to an alkyl or alkenyl group, the broadest range described in these definitions is to be assumed.
[0059] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that includes a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; for example, "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and/or including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of the compounds may be designated as "C1-C4 alkyl" or similar designations. By way of example only, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl chain, e.g., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and/or hexyl. The alkyl group may be substituted or unsubstituted.
[0060] As used herein, "alkenyl" refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. An alkenyl group may be unsubstituted or substituted.
[0061] The term "halogen" as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and/or iodine.
[0062] Whenever a group is described as being "optionally substituted" that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being "unsubstituted or substituted" if substituted, the substituent may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated "optionally substituted" or "substituted" group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono- substituted amino group and/or di- substituted amino group, and/or protected derivatives thereof.
[0063] The term "naphthoquinone analog" refers to a compound of Formula (I) wherein R1, R2, R3, R4, R5, and R6 are as defined herein.
[0064] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and/or phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and/or salts with amino acids such as arginine and/or lysine.
[0065] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be diastereometrically pure, diastereometrically enriched, or may be stereoisomeric mixtures. In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.
[0066] The term "pharmaceutical composition" refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and/or salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration. [0067] The term "physiologically acceptable" defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound.
[0068] A "pharmaceutically acceptable carrier" refers to a substance, not itself a therapeutic agent, which may facilitate the incorporation of a compound into cells or tissues. The carrier may be a liquid for the dissolution of a compound to be administered by ingestion. The carrier may be a vehicle for delivery of a therapeutic agent to a subject. The carrier may improve the stability, handling, or storage properties of a therapeutic agent. The carrier may facilitate formation of a dose unit of a composition into a discrete article such as a capsule, tablet, film coated tablet, caplet, gel cap, pill pellet, or bead, and the like suitable for oral administration to a subject.
[0069] As used herein, a "diluent" refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that is physiologically compatible with human cells and tissues.
[0070] As used herein, an "excipient" refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, or disintegrating ability etc., to the composition. A "diluent" is a type of excipient.
[0071] As used herein, a "subject" refers to an animal that is the object of treatment, inhibition, or amelioration, observation or experiment. "Animal" includes cold- and warm-blooded vertebrates and/or invertebrates such as fish, shellfish, or reptiles and, in particular, mammals. "Mammal" includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and/or apes, and, in particular, humans. In some embodiments, the subject is human.
[0072] Some embodiments disclosed herein related to selecting a subject or patient in need. In some embodiments, a patient is selected who is in need of treatment of cancer, such as a bladder cancer or a prostate cancer. In some embodiments, a patient is selected who has previously been treated for cancer, such as bladder cancer or prostate cancer. In some embodiments, a patient is selected who has previously been treated for being at risk of cancer, such as bladder cancer or prostate cancer. In some embodiments, a patient is selected who has developed a recurrence of cancer, such as bladder cancer or prostate cancer. In some embodiments, a patient is selected who has developed resistance to therapies for cancer, such as bladder cancer or prostate cancer. In some embodiments, a patient is selected who may have any combination of the aforementioned selection criteria.
[0073] As used herein, the terms "treating," "treatment," "therapeutic," or "therapy" do not necessarily mean total cure or abolition of the disease or condition.
[0074] As used herein, the term "inhibit" refers to the reduction or prevention of the growth of a cancer, such as bladder cancer or prostate cancer. The reduction can be by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or an amount that is within a range defined by any two of the aforementioned values. As used herein, the term "delay" refers to a slowing, postponement, or deferment of an event, such as the growth of a cancer, such as bladder cancer or prostate cancer, to a time which is later than would otherwise be expected. The delay can be a delay of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%), or an amount within a range defined by any two of the aforementioned values. The terms inhibit and delay are not to be construed as necessarily indicating a 100% inhibition or delay. A partial inhibition or delay may be realized.
[0075] The term "therapeutically effective amount" is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, a therapeutically effective amount of compound can be the amount needed to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being administered the therapy. This response may occur in a tissue, system, animal, or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
[0076] As used herein, the term "derivative" refers to a chemically modified compound wherein the modification is considered routine by the ordinary skilled chemist, such as an ester or an amide of an acid, or protecting groups such as a benzyl group for an alcohol or thiol, or a tert-butoxycarbonyl group for an amine.
[0077] As used herein, the term "analogue" refers to a compound, which includes a chemically modified form of a specific compound or class thereof and which maintains the pharmaceutical and/or pharmacological activities characteristic of said compound or class.
[0078] As used herein, "biosimilar" (of an approved reference product/biological drug, such as a protein therapeutic, antibody, etc.) refers to a biologic product that is similar to the reference product based upon data derived from (a) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (b) animal studies (including the assessment of toxicity); and/or (c) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product. In one embodiment, the biosimilar biological product and reference product utilize the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product. In one embodiment, the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product. In one embodiment, the route of administration, the dosage form, and/or the strength of the biological product are the same as those of the reference product. In one embodiment, the facility in which the biological product is manufactured, processed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure, and potent.
[0079] In some embodiments, the compositions herein are prepared or administered in a product combination e.g., with a compound of Formula (I) in combination with another therapeutic agent or therapy. Additional therapeutic agents and/or therapies that can be provided with a compound of Formula (I) include for example, an androgen deprivation agent or therapy, an anti-estrogen agent or therapy, a biological agent or therapy, a virus-based agent or therapy, surgery, a chemotherapeutic agent or chemotherapy, such as a taxane-based chemotherapy agent, an antineoplastic agent, such as a platinum-based antineoplastic agent, radiation or radiation therapy, a statin or a statin therapy, a repurposed drug or a repurposed drug therapy, a small molecule inhibitor or a small molecule inhibitor therapy, a therapeutic antibody or a therapeutic antibody therapy, a CAR T cell or a CAR T cell therapy, an immunotherapeutic agent or an immunotherapy, or any combination thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
[0080] In some embodiments, the compositions described herein are prepared or administered in a product combination, for example, with a compound of Formula (I) in combination with a hormone deprivation therapy. A hormone deprivation therapy may include, for example, an androgen deprivation therapy or an anti-estrogen agent or therapy. A hormone deprivation therapy may include a therapy, such as a surgical procedure, or administration of an agent.
[0081] As used herein, the term "androgen deprivation therapy" (ADT) refers to a treatment or amelioration of a disease or condition in which the level of androgen hormones in a patient are reduced, typically by surgical or pharmaceutical methods. Surgical methods of ADT include surgical orchiectomy. Pharmaceutical methods of ADT include administration of an agent, including orteronel, cyproterone acetate, flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, galeterone, abiraterone, finasteride, ethylstilbestrol (DES), megestrol acetate, fosfestrol, estramustine phosphate, leuprolide, triptorelin, goserelin, histrelin, buserelin, abarelix, degarelix, or derivatives, salts, or analogues thereof, or combinations thereof.
[0082] As used herein, the term "anti -estrogen therapy" or estrogen deprivation agent (anti-ER therapy) refers to a treatment or amelioration of a disease or condition in which the level of estrogen hormones in a patient are reduced, typically by surgical or pharmaceutical methods. Surgical methods of anti-ER therapy include surgical ovariectomy. Pharmaceutical methods of anti-ER include administration of tamoxifen, clomifene, ormeloxifene, toremifene, lasofoxifene, ospemifene, raloxifene, fulvestrant, brilanestrant, elacestrant, anastrozole, letrozole, testolactone, exemestane, or derivatives, salts, or analogues thereof, or combinations thereof.
[0083] As used herein, the term "biologic" or "biological agent" refer to any chemical or biochemical compound produced by a living organism, which can include a prokaryotic cell line, a eukaryotic cell line, a mammalian cell line, a microbial cell line, an insect cell line, a plant cell line, a mixed cell line, a naturally occurring cell line, or a synthetically engineered cell line. A biologic can include large macromolecules such as proteins, polysaccharides, lipids, and/or nucleic acids, as well as small molecules such as primary metabolites, secondary metabolites, and/or natural products. In some embodiments, a biologic includes Bacillus Calmette-Guerin (BCG) vaccine, sargramostim, filgrastim, pegfilgrastim, recombinant interleukin-12, or interferon alpha, or a combination thereof.
[0084] As used herein, the term "virus-based therapy" refers to the use of virus or virus like particles for use in the treatment, inhibition, or amelioration of a disease or condition. In some embodiments, a virus-based therapy includes use of a reovirus, bunyavirus, flavivirus, rubivirus, filovirus, arenavirus, arterivirus, or calicivirus. In some embodiments, a virus-based therapy includes a retrovirus, an adenoviral vector, (including the oncolytic adenovirus vector CG0070 (Cold Genesys)), or a Coxsackievirus A21 (CVA21; CAVATAK, Viralytics), or a combination thereof.
[0085] As used herein the term "chemotherapy" refers to any therapy that includes natural or synthetic chemotherapeutic agents now known or to be developed in the medical arts. Examples of chemotherapeutic agents include the numerous cancer drugs that are currently available. However, chemotherapy also includes any drug, natural or synthetic, that is intended to treat, inhibit, or ameliorate a disease state, such as cancer e.g., bladder cancer or prostate cancer. In certain embodiments, chemotherapy may include the administration of several state of the art drugs intended to treat, inhibit, or ameliorate the disease state, such as cancer e.g., bladder cancer or prostate cancer. In some embodiments, a chemotherapy comprises gemcitabine, cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, mustine, vincristine, procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, etoposide, epirubicin, capecitabine, methotrexate, folinic acid, lenalidomide, pemetrexed, azacitidine and analog decitabine, mitomycin C, apaziquone, eribulin, valrubicin, vinflunine, pirarubicine, pralatrexate, temsirolimus, sirolimus, ifosfamide, irinotecan, rubitecan, or AZD4877, or any combination thereof. In some embodiments, the chemotherapy is a taxane-based chemotherapy. In some embodiments, the chemotherapy is a platinum-based antineoplastic chemotherapy. In some embodiments, the chemotherapeutic agent or chemotherapy is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy.
[0086] Taxanes are a class of diterpenoid drugs that have anti-tumor activity against a wide range of human cancers. Paclitaxel was originally isolated from the bark of the Yew tree, and was known to act by interfering with the normal function of microtubule breakdown. Paclitaxel binds to the β subunit of tubulin, the building blocks of microtubules, causing hyper-stabilization of the microtubule structures. The resulting paclitaxel/microtubule structure is unable to disassemble, thereby arresting mitosis and inhibiting angiogenesis. In some embodiments, a taxane-based chemotherapy comprises docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or combinations, analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof.
[0087] An antineoplastic agent is an agent that inhibits or prevents the growth and/or spread of tumors or malignant cells, and may include, for example, nucleoside analogues, antifolates, antimetabolites, enzyme inhibitors such as topoisomerase I inhibitors, anthracyclines, podophyllotoxins, alkaloids, alkylating agents, platinum compounds, antibodies, tyrosine kinase inhibitors, mTOR inhibitors, retinoids, immunomodulatory agents, histone deacetylase inhibitors. Thus, an antineoplastic agent may include, for example, afatinib, aflibercept, alemtuzumab, alitretinoin, altretamine, anagrelide, arsenic trioxide, asparaginase, axitinib, azacitidine, BCG vaccine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, capecitabine, carboplatin, carmofur, carmustine, cetuximab, chlorambucil, chlormethine, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dasatinib, daunorubicin, decitabine, denileukin diftitox, denosumab, docetaxel, doxorubicin, epirubicin, erlotinib, estramustine, etoposide, everolimus, floxuridine, fludarabine, fluorouracil, fotemustine, gefitinib, gemcitabine, gemtuzumab ozogamicin, hydroxycarbamide, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, ipilimumab, irinotecan, isotretinoin, ixabepilone, lapatinib, lenalidomide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, nedaplatin, nelarabine, nilotinib, nivolumab, ofatumumab, oxaliplatin, paclitaxel, panitumumab, panobinostat, pazopanib, pembrolizumab, pemetrexed, penostatin, pertuzumab, pomalidomide, ponatinib, procarbazine, raltitrexed, regorafenib, ritixumab, romidepsin, ruxolitinib, sorafenib, streptozotocin, sunitinib, tamibarotene, tegafur, temozolomide, temsirolimus, teniposide, thalidomide, tioguanine, topotecan, tositumomab, trastuzumab, tretinoin, valproate, valrubicin, vandetanib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vemurafenib, or vorinostat. Platinum compounds, for example, platinum-based antineoplastic agents are a class of platinum containing agents for use in cancer treatment, and are platinum based alkylating agents. Platinum-based antineoplastic agents inhibit DNA repair and/or DNA synthesis in cells, including cancer cells. In some embodiments, the platinum-based antineoplastic chemotherapy comprises cisplatin, carboplatin, dicycloplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, or satraplatin, or analogues or derivatives thereof.
[0088] As used herein, the term "radiation therapy" (also known as radiation oncology or radiotherapy) refers to the medical use of ionizing radiation as part of a cancer therapy designed to kill malignant cells that are progressing through the cell cycle (e.g., in any phase of the cell cycle). The radiation therapy may be internal or external radiotherapy. External radiotherapy involves targeting doses (or "fractions") of high-energy beams of radiation, either X-rays or gamma rays, to the tumor. Internal radiotherapy involves positioning the source of radioactivity inside the body close to the tumor. This can be achieved in two ways: by brachytherapy or by radioisotope therapy. Brachytherapy involves placing a solid source of radiation next to a tumor to give a high dose of radiotherapy. Radioisotope therapy involves administration of a radioactive substance, a radioisotope, either as an intravenous injection, or as an oral capsule or liquid.
[0089] As used herein, the term "statin" refers to any of a class of lipid-lowering drugs that reduce serum cholesterol levels by inhibiting HMG-CoA reductase, a key enzyme involved in the biosynthesis of cholesterol, the mevalonate pathway or HMG-CoA reductase pathway. Non-limiting examples of statins can comprise atorvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and/or simvastatin, or combinations thereof, or a combination of a statin and another agent, such as ezetimibe/simvastatin.
[0090] As used herein, the term "repurposed drug therapy" refers to a strategy by which a new or additional value is generated from a drug by targeting a disease other than those diseases for which the drug was originally intended. In some embodiments, a repurposed drug therapy comprises but is in no way limited to eflornithine, indinavir, metformin, or ritonavir, or a combination thereof.
[0091] As used herein, the term "small molecule inhibitor therapy" refers to small organic molecules, peptides, antibodies, cyclic peptides and/or peptidomimetics that are small molecules, such as less than 10,000 Daltons (but not zero), and that act by inhibition, now known or to be developed in the medical arts. In some embodiments, a small molecule inhibitor therapy comprises belinostat, bortezomib, copanlisib, crizotinib, imatinib, dasatinib, dovitinib, rapamycin, everolimus, sirolimus, tipifarnib, pazopanib, alisertib, sapanisertib, lapatinib, lonafarnib, merestinib, olaparib, palbociclib, bosutinib, sorafenib, erlotinib, sunitinib, cabozantinib, gefitinib, ixazomib, vistusertib, vorinostat, entinostat vandetanib, BAY1163877, MLN8054, PLX3397, or BGJ398, or any combination thereof.
[0092] As used herein, the term "therapeutic antibody therapy" refers to any antibody, now known or to be developed in the medical arts, which can be administered to a subject as an active agent, including derivatives and fragments thereof, or antigen-specific ligand molecules, such as antibody Fab fragments, or antibody Fc fragments, synthetic receptors, or soluble receptors, which selectively bind a target antigen. In some embodiments, a therapeutic antibody therapy comprises cetuximab, ritixumab, bevacizumab, ranibizumab, trastuzumab, or panitumumab, fragments thereof, or any combination thereof, which may be presented on one or more CAR T cells.
[0093] As used herein, the term "immunotherapy" refers to a therapy now known or to be developed in the medical arts for a disease that relies on an immune response. In some embodiments, an immunotherapy comprises nivolumab, durvalumab, pembrolizumab, atezolizumab, ipilimumab, tremelimumab, CA-170, NEO-PV-01, or a tumor cell-derived vaccine therapy, or any combination thereof. [0094] As used herein, the term "coadministration" of pharmacologically active compounds refers to the delivery of two or more separate chemical entities, whether in vitro or in vivo. Coadministration refers to the simultaneous delivery of separate agents; to the simultaneous delivery of a mixture of agents; as well as to the delivery of one agent followed by delivery of a second agent or additional agents. In all cases, agents that are coadministered are intended to work in conjunction with each other. Similarly, in the context of administration of more than one compound, the term "in combination" refers to a concomitant delivery of one compound with one or more compounds. The compounds may be administered in combination by simultaneous administration or administration of one compound before or after administration of another compound, such as within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 minutes or within a range defined by any two of the aforementioned time points.
[0095] As used herein, the term "cancer" refers to a class of diseases of humans (and animals) characterized by uncontrolled cellular growth. As used herein, "cancer" is used interchangeably with the terms "tumor," "malignancy," "hyperproliferation" and "neoplasm(s) ." The term "cancer cell(s)" is interchangeable with the terms "tumor cell(s)," "malignant cell(s)," "hyperproliferative cell(s)," and "neoplastic cell(s)" unless otherwise explicitly indicated. Similarly, the terms "hyperproliferative," "hyperplastic," "malignant" and "neoplastic" are used interchangeably, and refer to those cells in an abnormal state or condition characterized by rapid proliferation. Collectively, the terms "cancer," "tumor," "malignancy," "hyperproliferation" and "neoplasm(s)" are meant to include all types of hyperproliferative growth, hyperplastic growth, neoplastic growth, cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness.
[0096] As used herein "bladder cancer" refers to cellular carcinomas characterized by uncontrolled cell growth of bladder cells. One form of bladder cancer includes urothelial cell carcinoma, which is a malignancy of the specialized transitional epithelium lining the organ. Urothelial cell carcinomas of the bladder (UCCB) are classified into two categories termed non-muscle invasive bladder cancer and muscle invasive bladder cancer. Non-muscle invasive bladder cancer is highly treatable, usually by complete resection of the tumor followed by immunotherapy with intra-vesical BCG vaccine or intra- vesical chemotherapy. Other forms of bladder cancer include squamous cell carcinoma, adenocarcinoma, sarcoma, small cell carcinoma, and/or secondary deposits from cancers elsewhere in the body. Bladder cancer may include transitional cell carcinoma, squamous cell carcinoma, and/or adenocarcinomas of the bladder.
[0097] As used herein "prostate cancer" refers to cellular carcinomas characterized by uncontrolled cell growth of prostate cells. Prostate cancer may include malignant mammalian cancers, including adenocarcinomas, derived from prostate epithelial cells. Prostate cancers described in the current application may include both metastatic and non-metastatic cancers.
[0098] As used in this specification, whether in a transitional phrase or in the body of the claim, the terms "comprise(s)" and "comprising" are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases "having at least" or "including at least." When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition or device, the term "comprising" means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. The section below describes some of the compounds that can be used to treat cancer, or inhibit or delay the growth of cancer cells, especially bladder cancer cells alone or in combination with one or more androgen deprivation therapies (e.g., castration, hormonal castration, hormonal ablation, or hormone therapy).
II. Bladder Cancer
[0099] The main risk factors for bladder cancer are smoking (worldwide) and infection with Schistosoma haematobium (in parts of Northern and sub-Saharan Africa). However, hormonal factors play a role as well, as evidenced by the considerable difference in the incidence of bladder cancer between men and women. Indeed, about 75% of bladder cancer cases occur in men, and is three times more likely to present in men than in women. The gender disparity is independent of differences in exposure risk, including smoking status between sexes. Hemelt et al., Int J Cancer ; 2009, 124, 412-419. On the other hand, women diagnosed with bladder cancer have higher risks of recurrence, progression and mortality than men. [0100] Recent studies have shown that androgen receptor (AR) and androgens play a role in the development of bladder tissue and that alteration of AR expression and signaling can influence the initiation or the growth of bladder tumors in animal models. Li et al., Jap J Clin Oncol, 2012, 42, 569-577; Lombard et al., Endocrinol, 2015, 22, R265-R277; Mizushima et al., Expert Ipin Ther Targets, 2017, 19, 1-9. Data suggest that androgen signaling plays a role in both male and female, however the increased predisposition to bladder cancer observed in men compared to women is consistent with the fact that males have higher AR expression and higher levels of circulating androgens. Nonetheless, androgens are present in women as well and play major physiological roles. Androgens are, in fact, present in higher amounts than estrogens in the female body and serve as precursors for estrogens.
[0101] Several lines of evidence have given the present inventors the concept that AR and androgens play a role in bladder cancer:
[0102] 1) AR is expressed in bladder epithelial cells and its expression is increased in tumor cells compared to normal cells in human tissue. Lombard et al., Endocrinol, 2015, 22, R265-R277.
[0103] 2) Treatment with testosterone DHT increases the proliferation of various bladder cancer cell lines that express AR. Johnson et al., BMC Urol, 2008, 8, 7; Kawahara et al., Urol Oncol, 2016, 34, 432. Silencing of AR decreases the proliferation and migration of bladder cancer cells. Wu et al., Urol, 2010, 75, 820-827; Ding et al., Am J Transl Res, 2016, 8, 578-587. In addition, AR antagonists such as enzalutamide, flutamide and bicalutamide inhibit cell proliferation and invasion in AR-positive cells (Miyamoto et al., J Natl Cancer Inst, 2007, 99, 558-568; Kawahara et al., Urol Oncol, 2016, 34, 432.
[0104] 3) Castration, androgen-deprivation therapy (ADT) drugs and AR antagonists decrease the incidence of carcinogen-induced bladder cancer in mice, decrease the growth of bladder tumors in a transgenic mouse model or in xenograft models. Imada et al., Eur Urol, 1997, 31, 360-364; Johnson et al., BMC Urol, 2008, 8, 7; Miyamoto et al., J Natl Cancer Inst, 2007, 99, 558-568; Kawahara et al., Urol Oncol, 2016, 34, 432. On the other hand, AR overexpression promotes tumor metastasis in xenograft models. Jing et al., Cancer Lett, 2014, 348, 135-145. [0105] 4) Both male and female AR-knockout mice (ARKO mice) are protected from carcinogen-induced bladder cancer. Miyamoto et al., J Natl Cancer Inst, 2007, 99, 558- 568. In addition, the development of bladder tumors is decreased and overall survival is increased in mice in which AR was suppressed specifically in urothelial tissue. Hsu et al., Am J Pathol, 2013, 182, 1811-1820.
[0106] 5) A retrospective analysis of patients with cancer of the prostate, as well as, cancer of the bladder who received or did not receive ADT revealed that patients who received ADT had fewer bladder cancer recurrence than patients who did not, and a higher 5- year survival rate. Izumi, Oncotarget, 2014, 5, 12665-12674.
[0107] Bladder cancer is categorized in various stages, including stage 0a (including non-invasive papillary carcinoma, no regional lymph node metastasis, and no distant metastasis); stage Ois (including carcinoma in situ (flat tumor), no regional lymph node metastasis, and no distant metastasis); stage I (including tumor invasion of subepithelial connective tissue, no regional lymph node metastasis, and no distant metastasis); stage II (including tumor invasion of superficial muscle (inner half) or tumor invasion of deep muscle (outer half), no regional lymph node metastasis, and no distant metastasis); stage III (including tumor invasion of perivesical tissue on a microscopic or macroscopic level, tumor invasion of prostate, uterus, or vagina, no regional lymph node metastasis, and no distant metastasis); stage IV (including any of stages 0a, Ois, I, II, or III, tumor invasion of pelvic wall or abdominal wall, metastasis in a single lymph node from less than 2 cm to greater than 5 cm, distant metastasis); and high risk non-muscle invasive bladder cancer (including any transitional cell carcinoma of the bladder that is high-grade, including primary or recurrent).
[0108] As disclosed herein, the AR axis is a therapeutic target for bladder cancer. As shown in Figures 1 and 2, a compound of Formula (I) acts as an antagonist to AR by decreasing AR expression. As shown herein, compositions including a compound of Formula (I) also have anti-proliferation activity in bladder cancer. Figure 1 depicts a dose-dependent decrease in AR in prostate cancer cell lines is observed when contacting mouse prostate cancer cells (PTEN-P2 cells) and human cancer cells (LNCaP cells) grown in the presence of 10"8 M DHT, and the incubated with increasing concentrations of a compound of Formula
(I). [0109] Metastatic bladder cancers are sometimes treated with platinum-based agents. Despite initial sensitivity to cisplatin-based chemotherapy regimens, long term control rates of advanced or metastatic disease remain less than 5%. There is currently no standard second-line chemotherapy for metastatic urothelial cancer previously treated with a platinum-based regimen. In this setting, paclitaxel and docetaxel are commonly used despite overall response rates of less than 20%.
[0110] Gemcitabine and cisplatin-based chemotherapy (GC) is a standard treatment for metastatic or recurrent bladder cancer, however its efficacy is limited by the rapid emergence to resistance. It has been shown that AR expression in bladder cancer cells is associated with resistance to cisplatin in vitro, and that treatment of AR-positive cells with androgens decreases cisplatin sensitivity (Kashiwagi et al., Oncotarget, 2016, 7, 49169- 49179).
[0111] Recurrence rate of bladder cancer also presents an additional challenge for bladder cancer treatment. For example, up to 50% of patients treated with BCG (bacillus Calmette-Guerin) for non-muscle-invasive bladder cancer will experience a recurrence within five years. Repeated courses of BCG treatment lead to up to 80% failure rates. Response rates to current second line intravesical therapies average less than 20%.
[0112] Unfortunately, should recurrence of bladder cancer or resistance of bladder cancer to current treatments occur, no curable treatments exist to counter the recurrence or resistance.
[0113] Thus, all current hormonal, as well as chemotherapy treatment regimens for such recurrent or resistant bladder cancers are palliative. Accordingly, provided herein are methods and compositions useful for the treatment of bladder cancer. In some embodiments, the methods and compositions are useful for the treatment or inhibition of bladder cancer that has developed resistance to therapies, for example, androgen deprivation therapies, antineoplastic agents, chemotherapies, radiation therapies, surgical therapies, or other therapies, optionally, wherein the chemotherapy or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
[0114] In some embodiments, the methods and compositions provided herein provide surprising and unexpected improvements in the treatment or inhibition of bladder cancer, including in subjects that have developed resistance to therapies of bladder cancer. In one embodiment, for example, the targeting of AR during chemotherapy is a surprising and unexpected strategy to overcome or delay the acquisition of GC resistance in patients with AR-positive bladder cancer.
[0115] AR expression was up-regulated in cells rendered resistant to cisplatin in vitro, while analysis of human clinical specimen showed a correlation between AR levels and cisplatin resistance (Kashiwagi et al., Oncotarget, 2016, 7, 49169-49179). In another study, upregulation of AR expression was observed in gemcitabine-resistant cells compared to non- resistant cells and treatment with AR antagonist enzalutamide inhibited the proliferation of the resistant cell lines (Kameyama et al. Int J Oncol, 2017, 50, 75-84). The section below provides more details on the use of compounds of Formula (I) to inhibit or delay the growth of cancer cells, in particular, bladder cancer cells.
III. Prostate Cancer
[0116] There were an estimated 192,280 new cases of prostate cancer diagnosed in the U.S. in 2009 and an estimated 27,360 deaths. About 90% of patients with advanced disease will develop bone metastases, associated with severe pain, loss of mobility, and spinal cord compression. Other affected organs may include the liver, lungs and brain. Advanced prostate cancer is resistant to hormone therapy, radiation and conventional chemotherapy. Although the 5-year survival rate is close to 100% for local disease, it drops to 30%) for advanced cancer.
[0117] In the initial stages, prostate tumor growth is androgen dependent. Androgens are used by prostate cancer cells for both proliferation as well as regulation, and are vital for maintaining the growth and survival of the cancer cell. The main androgen that circulates is testosterone, which is mainly produced in the testes. Extragonadal sources of androgen synthesis do, however, exist and may play a role in the development of castration- resistant forms of prostate cancer. Generally, androgen dependent prostate cancer therapy focuses on minimizing testicular synthesis of androgens with luteinizing hormone releasing hormone ("LHRH") agonists or antagonists. Some therapies also focus on modulating the androgen receptor itself, or its downstream signaling pathway.
[0118] Androgen dependent prostate cancer will eventually progress into castration-resistant prostate cancer ("CRPC"). Although these patients are "androgen insensitive," researchers have discovered that androgen-responsive genes are still expressed, implying that the androgen-receptor signaling pathway may still be an important target in CRPC patients. Schweizer et al., Therapeutic Advances in Urology, 4(4), 167-178.
[0119] There have been some advances in the treatment of prostate cancer recently, including new surgical approaches and improvements in radiotherapy. For example:
[0120] 1) In 1986, surgeons developed a technique (using da Vinci Prostatectomy) that allowed the removal of the prostate while minimizing nerve damage, thereby decreasing adverse side effects.
[0121] 2) In addition, clinical researchers improved a long-established radiotherapy technique known as brachytherapy, which involves the implantation of a small amount of radioactive material (seeds) into the prostate. This radiation therapy method is an effective treatment for early-stage prostate cancer.
[0122] 3) There have also been advances in hormonal therapy for prostate cancer including the development of gonadotropin-releasing hormone (GnRH) agonists, which inhibit the ability of the pituitary gland to stimulate the testes to make testosterone.
[0123] 4) Advances have also been made in chemotherapy for prostate cancer. In 2004, results from two large NCI-sponsored clinical trials showed that use of the drug docetaxel could prolong the survival of men who had advanced prostate cancer which no longer responded to hormonal therapy.
[0124] Unfortunately, should the prostate-specific antigen (PSA) level remain above zero after radical prostatectomy is performed, with conventional therapy or with advanced therapy using da Vinci Prostatectomy, this indicates that the prostate cancer has spread outside the capsule, for example, disseminated disease, and to date, there is no curable treatment for this.
[0125] Thus, all current hormonal and chemotherapy treatment regimens for such disseminated androgen dependent prostate cancers are palliative. Subsequently, even if there have been advances in the treatment of prostate cancer, finding new strategies for treatment of disseminated disease remains a crucial challenge.
[0126] The section below provides more details on the use of compounds of Formula (I), alone or in combination with taxane-based chemotherapy agents or platinum- based antineoplastic agents to inhibit, ameliorate, prevent, or delay the growth of cancer cells, in particular bladder cancer cells or prostate cancer cells.
IV. Pharmaceutical compositions of Compound of Formula (I)
[0127] The present disclosure relates to pharmaceutical compositions containing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and methods of using these compounds alone or in combination with an additional therapy or therapeutic agent to inhibit, delay, treat, or prevent cancer cell growth or cancer, such as bladder cancer or prostate cancer, in a subject in need thereof. Other embodiments disclosed herein relate to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, alone or in combination with an additional therapy or therapeutic agent, to inhibit, delay, treat, or prevent cancer cell growth or cancer, such as bladder cancer or prostate cancer, in a subject in need thereof. Other embodiments disclosed herein relate to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, alone or in combination with a therapeutic agent, in the manufacture of a medicament for inhibiting, delaying, treating, or preventing cancer cell growth or cancer, such as bladder cancer or prostate cancer, in a subject in need thereof. Other embodiments, disclosed herein relate to a product combination and/or the use of a product combination containing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a therapeutic agent, as described herein, to inhibit, delay, treat, or prevent cancer cell growth or cancer, such as bladder cancer or prostate cancer, in a subject in need thereof and/or for the manufacture of a product combination for inhibiting, delaying, treating, or preventing cancer cell growth or cancer, such as bladder cancer or prostate cancer, in a subject in need thereof.
[0128] In some embodiments, the compound of Formula (I) has the following structure:
Figure imgf000039_0001
wherein: R1 can be selected from hydrogen, halogen, an optionally substituted C1-18 alkyl, an optionally substituted C2-18 alkenyl, -OR7 and -SR8; R2 can be selected from hydrogen, halogen, an optionally substituted Ci-6 alkyl, an optionally substituted C2-6 alkenyl, -OR9 and -SR10; R3 can be selected from hydrogen, an optionally substituted Ci-6 alkyl, and -OR11; R4 can be selected from hydrogen, an optionally substituted Ci-6 alkyl, and -OR12; R5 can be selected from hydrogen, an optionally substituted Ci-6 alkyl, and -OR13; R6 can be selected from hydrogen, an optionally substituted Ci-e alkyl, and -OR14; and R7, R8, R9, R10, R11, R12, R13, and R14 can be independently selected from hydrogen and an optionally substituted Ci-6 alkyl.
[0129] In some embodiments, R1 can be hydrogen. In some embodiments, R1 can be halogen. In some embodiments, R1 can be chloro. In some embodiments, R1 can be an optionally substituted C1-18 alkyl. Examples of optionally substituted Ci-is-alkyls include, but are not limited to, optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decanyl, undecanyl, dodecanyl, tridecanyl, tetradecanyl, pentadecanyl, hexadecanyl, heptadecanyl, octadecanyl, and phytanyl. Optionally substituted Ci-is-alkyls can be branched or straight- chained. In some embodiments, R1 can be an optionally substituted Ci-6 alkyl. In some embodiments, R1 can be methyl. In some embodiments, R1 can be t-butyl. In some embodiments, R1 can be an optionally substituted C2-18 alkenyl. Examples of optionally substituted C2-is-alkenyls include, but are not limited to, optionally substituted variants of the following: ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, and phytenyl. Optionally substituted C2-is-alkenyls can be branched or straight-chained, and can include one or more double bonds. In some embodiments, R1 can be an optionally substituted C2-6 alkenyl. In some embodiments, R1 can be -OR7, wherein R7 is hydrogen. In some embodiments, R1 can be -OR7, wherein R7 is an optionally substituted Ci-6 alkyl. In some embodiments, R1 can be -OR7, wherein R7 is methyl. In some embodiments, R1 can be -SR8, wherein R8 is hydrogen. In some embodiments, R1 can be -SR8, wherein R8 is an optionally substituted Ci-6 alkyl. In some embodiments, R1 can be -SR8, wherein R8 is Ci-6 alkyl optionally substituted with hydroxy. In some embodiments, R1 can be -SR8, wherein R8 is -CH2CH2OH. [0130] In some embodiments, R2 can be hydrogen. In some embodiments, R2 can be halogen. In some embodiments, R2 can be chloro. In some embodiments, R2 can be an optionally substituted Ci-6 alkyl. Examples of optionally substituted Ci-6-alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight- chained). In some embodiments, R2 can be methyl. In some embodiments, R2 can be an optionally substituted C2-6 alkenyl. Examples of optionally substituted C2-6-alkenyls include optionally substituted variants of the following: ethenyl, propenyl, butenyl, pentenyl (branched and straight-chained), and hexenyl (branched and straight-chained). In some embodiments, R2 can be -CH2-CH=C(CH3)2. In some embodiments, R2 can be -OR9, wherein R9 is hydrogen. In some embodiments, R2 can be -OR9, wherein R9 is an optionally substituted Ci-6 alkyl. In some embodiments, R2 can be -OR9, wherein R9 is methyl. In some embodiments, R2 can be -SR10, wherein R10 is hydrogen. In some embodiments, R2 can be - SR10, wherein R10 is an optionally substituted Ci-6 alkyl. In some embodiments, R2 can be - SR10, wherein R10 is Ci-6 alkyl optionally substituted with hydroxy. In some embodiments, R2 can be -SR10, wherein R10 is -CH2CH2OH.
[0131] In some embodiments, R3 can be hydrogen. In some embodiments, R3 can be an optionally substituted Ci-6 alkyl. In some embodiments, R3 can be -OR11, wherein R11 is hydrogen. In some embodiments, R3 can be -OR11, wherein R11 is an optionally substituted Ci-6 alkyl.
[0132] In some embodiments, R4 can be hydrogen. In some embodiments, R4 can be an optionally substituted Ci-6 alkyl. In some embodiments, R4 can be t-butyl. In some embodiments, R4 can be -OR12, wherein R12 is hydrogen. In some embodiments, R4 can be - OR12, wherein R12 is an optionally substituted Ci-6 alkyl.
[0133] In some embodiments, R5 can be hydrogen. In some embodiments, R5 can be an optionally substituted Ci-6 alkyl. In some embodiments, R5 can be -OR13, wherein R13 is hydrogen. In some embodiments, R5 can be -OR13, wherein R13 is an optionally substituted Ci-6 alkyl.
[0134] In some embodiments, R6 can be hydrogen. In some embodiments, R6 can be an optionally substituted Ci-6 alkyl. In some embodiments, R6 can be -OR14, wherein R14 is hydrogen. In some embodiments, R6 can be -OR14, wherein R13 is an optionally substituted Ci-6 alkyl.
[0135] In some embodiments, R7, R8, R9, R10, R11, R12, R13, and R14 can be independently selected from hydrogen. In some embodiments, R7, R8, R9, R10, R11, R12, R13, and R14 can be independently selected from Ci-6 alkyl. In some embodiments, R7, R8, R9, R10, R11, R12, R13, and R14 can be independently selected from Ci-6 alkyl, wherein the Ci-6 alkyl can be optionally substituted with a group selected from halogen, hydroxy, and Ci-4 alkyl.
[0136] In some embodiments, R1 can be selected from hydrogen, halogen, an optionally substituted Ci-6 alkyl, -OR7 and -SR8; R2 can be selected from hydrogen, halogen, an optionally substituted Ci-6 alkyl, -OR9 and -SR10; R3 can be selected from hydrogen and - OR11; R4 can be selected from hydrogen and an optionally substituted Ci-6 alkyl; R5 can be hydrogen; R6 can be selected from hydrogen and -OR14; and R7, R8, R9, R10, R11, R12, R13, and R14 can be independently selected from hydrogen and an optionally substituted Ci-6 alkyl.
[0137] In some embodiments, R1, R2, R3, R4, R5 and R6 can each be hydrogen. In some embodiments, R1 can be methyl; R3 can be -OH; and R2, R4, R5 and R6 can each be hydrogen. In some embodiments, R3 and R6 can each be -OH; and R1, R2, R4 and R5 can each be hydrogen. In some embodiments, R3 can be -OH; and R1, R2, R4, R5 and R6 can each be hydrogen. In some embodiments, R1 and R2 can each be -SCH2CH2OH; and R3, R4, R5 and R6 can each be hydrogen. In some embodiments, R1 and R2 can each be -OCH3; and R3, R4, R5 and R6 can each be hydrogen. In some embodiments, R1 can be -OCH3; and R2, R3, R4, R5 and R6 can each be hydrogen. In some embodiments, R1 can be methyl; and R2, R3, R4, R5 and R6 can each be hydrogen. In some embodiments, R1 and R2 can each be chloro; and R3, R4, R5 and R6 can each be hydrogen. In some embodiments, R1 can be -OH; and R2, R3, R4, R5 and R6 can each be hydrogen. In some embodiments, R1 can be phytenyl; R2 can be methyl; and R3, R4, R5 and R6 can each be hydrogen. In some embodiments, R1 and R4 can each be t-butyl; and R2, R3, R5 and R6 can each be hydrogen. In some embodiments, R1 can be -OH; R2 can be -CH2-CH=C(CH3)2; and R3, R4, R5 and R6 can each be hydrogen.
[0138] In some embodiments, at least one of R1, R2, R3, R4, R5 and R6 cannot be hydrogen. In some embodiments, when R1 is methyl; and R2, R4, R5 and R6 are each hydrogen; then R3 cannot be -OH. In some embodiments, when R1, R2, R4 and R5 are each hydrogen; then at least one of R3 and R6 cannot be -OH. In some embodiments, when R1, R2, R4, R5 and R6 are each hydrogen; then R3 cannot be -OH. In some embodiments, when R3, R4, R5 and R6 are each hydrogen; then at least one of R1 and R2 cannot be -SCH2CH2OH. In some embodiments, when R3, R4, R5 and R6 are each hydrogen; then at least one of R1 and R2 cannot be -OCH3. In some embodiments, when R2, R3, R4, R5 and R6 are each hydrogen; then R1 cannot be -OCH3. In some embodiments, when R2, R3, R4, R5 and R6 are each hydrogen; then R1 cannot be methyl. In some embodiments, when R3, R4, R5 and R6 are each hydrogen; then at least one of R1 and R2 cannot be chloro. In some embodiments, when R2, R3, R4, R5 and R6 are each hydrogen; then R1 cannot be -OH. In some embodiments, when R2 is methyl; and R3, R4, R5 and R6 are each hydrogen; then R1 cannot be phytenyl. In some embodiments, when R2, R3, R5 and R6 are each hydrogen; then at least one of R1 and R4 cannot be t-butyl. In some embodiments, when R2 is -CH2-CH=C(CH3)2; and R3, R4, R5 and R6 are each hydrogen; then R1 cannot be -OH.
[0139] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is prepared with a pharmaceutically acceptable carrier that facilitates the incorporation of a compound into cells or tissues. In some embodiments, the pharmaceutical composition including a compound of Formula (I) may include a compound of Formula (I), at least one pharmaceutically acceptable carrier, at least one excipient, and chemotherapeutic agent, or antineoplastic agent, optionally, wherein the chemotherapeutic agent or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy. In some embodiments, the at least one excipient may be a binder, a disintegrant, a surfactant, or a stabilizer.
V. Cancer Therapy Treatments
[0140] Cancer therapies, including existing therapies for cancer, such as bladder cancer or prostate cancer, may include a therapy comprising an androgen deprivation agent or therapy, an anti-estrogen agent or therapy, a biological agent or therapy, a virus-based agent or therapy, surgery, a chemotherapeutic agent or chemotherapy, such as a taxane-based chemotherapeutic agent, an antineoplastic agent, such as a platinum-based antineoplastic agent, radiation or radiation therapy, a statin or a statin therapy, a repurposed drug or a repurposed drug therapy, a small molecule inhibitor or a small molecule inhibitor therapy, a therapeutic antibody or a therapeutic antibody therapy, a CAR T cell or a CAR T cell therapy, an immunotherapeutic agent or an immunotherapy, or any combination thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy which can be provided to a subject in need thereof in addition to a compound of Formula (I). In some embodiments, a subject suffering from cancer, such as bladder cancer or prostate cancer is provided one or more of the aforementioned therapies before, after, or simultaneous with administration of a compound of Formula (I). In some embodiments, a cancer therapy contemplated herein can also comprise a standard of care cancer therapy treatment. Thus, some embodiments included herein may comprise a standard of care cancer therapy treatment in combination with a compound of Formula (I) with or without additional administration of an androgen deprivation agent or therapy, an anti-estrogen agent or therapy, a biological agent or therapy, a virus-based agent or therapy, surgery, a chemotherapeutic agent or chemotherapy, such as a taxane-based chemotherapeutic agent, an antineoplastic agent, such as a platinum-based antineoplastic agent, radiation or radiation therapy, a statin or a statin therapy, a repurposed drug or a repurposed drug therapy, a small molecule inhibitor or a small molecule inhibitor therapy, a therapeutic antibody or a therapeutic antibody therapy, a CAR T cell or a CAR T cell therapy, an immunotherapeutic agent or an immunotherapy, or any combination thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
[0141] In some embodiments, the compositions described herein are prepared or administered in a product combination, for example, with a compound of Formula (I) in combination with a hormone deprivation therapy. A hormone deprivation therapy may include, for example, an androgen deprivation therapy or an anti-estrogen agent or therapy. A hormone deprivation therapy may include a therapy, such as a surgical procedure, or administration of an agent.
[0142] Androgen deprivation therapies (ADT) include a therapy for a disease or condition in which the level of androgen hormones in a patient are reduced, typically by surgical or pharmaceutical methods. Surgical methods of ADT can comprise surgical orchiectomy, which refers to removal of the testes.
[0143] Pharmaceutical ADT therapies may comprise:
[0144] orteronel (including pharmaceutically acceptable salts thereof. Orteronel includes TAK-700. Orteronel includes 6-(7-Hydroxy-6,7-dihydro-5H-pyrrolo[l,2- c]imidazol-7-yl)-N-methyl-naphthalene-2-carboxamide);
[0145] cyproterone acetate (including pharmaceutically acceptable salts thereof, including Androcur and CYPROSTAT®. Cyproterone acetate can include lR,3aS,3bR,7aR,8aS,8bS,8cS,10aS)-l-acetyl-5-chloro-8b,10a-dimethyl-7-oxo- l,2,3,3a,3b,7,7a,8,8a,8b,8c,9, 10,10a-tetradecahydrocyclopenta-[a]cyclopropa- [g]phenanthren-l-yl acetate);
[0146] flutamide (including pharmaceutically acceptable salts thereof, including hydroxyflutamide and 2-amino-5-nitro-4-(trifluoromethyl)phenol. Flutamide includes Eulexin, Flutamin, Cytomid, Flutamide USP25, Cebatrol, Niftholide, and Niftolid. Flutamide includes 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide);
[0147] nilutamide (including pharmaceutically acceptable salts thereof. Nilutamide includes Nilandron and Anandron. Nilutamide includes 5,5-dimethyl-3-[4-nitro- 3-(trifluoromethyl)phenyl] imidazolidine-2,4-dione);
[0148] bicalutamide (including pharmaceutically acceptable salts thereof, including BICALOX®, CASODEX®, COSUDEX®, Calutide, and Kalumid. Bicalutamide includes N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2- methylpropanamide);
[0149] enzalutamide (including pharmaceutically acceptable salts thereof. Enzalutamide includes Xtandi (including Xtandi oral). Enzalutamide includes (4-(3-(4- cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro- N-methy lb enzami de));
[0150] apalutamide (including pharmaceutically acceptable salts thereof. Apalutamide includes 4-{7-[6-Cyano-5-(trifluoromethyl)-3-pyridinyl]-8-oxo-6-thioxo-5,7- diazaspiro[3.4]oct-5-yl}-2-fluoro-N-methylbenzamide); [0151] doralutamide (including pharmaceutically acceptable salts thereof. Doralutamide includes N-((S)-l-(3-(3-chloro-4-cyanophenyl)-lH-pyrazol-l-yl)propan-2-yl)- 5-(l-hydroxyethyl)-lH-pyrazole-3-carboxamide);
[0152] galeterone (including pharmaceutically acceptable salts thereof. Galeterone includes 17-(lH-benzimidazol-l-yl)androsta-5, 16-dien-3P-ol);
[0153] abiraterone (including pharmaceutically acceptable salts thereof, including abiraterone acetate. Abiraterone includes Abretone and ZYTIGA™. Abiraterone includes (3P)-17-(pyridin-3-yl)androsta-5,16-dien-3-ol. Abiraterone includes Abretone and ZYTIGA®);
[0154] finasteride (including pharmaceutically acceptable salts thereof. Finasteride includes MK-906, Proscar and Propecia. Finasteride includes N-(l,l- dimethylethyl)-3 -oxo-(5a, 17P)-4-azaandrost- 1 -ene- 17-carboxamide);
[0155] ethylstilbestrol (including diethylstilbestrol (including pharmaceutically acceptable salts thereof, including diethylstilbestrol disodium, diethylstilbestrol diphosphate, and Diethylstilbestrol dipropionate. Diethylstilboestrol includes DISTILBENE®, Stilbestrol, and Stilphostrol. Diethylstilboestrol includes 4,4'-(3E)-hex-3-ene-3,4-diyldiphenol) or ethylstilbestrol (including pharmaceutically acceptable salts thereof. Ethylstilboestrol includes BRN 3136095 and alpha-ethyl-4,4'-stilbenediol));
[0156] megestrol acetate (including pharmaceutically acceptable salts thereof. Megestrol acetate includes Megace and Megace ES. Megestrol acetate includes 17a- (acetyloxy)6-methylpregna-4,6-diene-3,20-dione);
[0157] fosfestrol (including pharmaceutically acceptable salts thereof, including fosfestrol sodium and fosfestrol tetrasodium. Fosfestrol includes fosfestrol, fosfestrolo, Honvan, and Stilbostatin. Fosfestrol includes [4-[4-(4-phosphonooxyphenyl)hex-3-en-3-yl] phenoxy]phosphonic acid and diethylstilbestrol diphosphate);
[0158] estramustine phosphate (including pharmaceutically acceptable slats thereof. Estramustine phosphate includes Emcyt and Estracyt. Estramustine phosphate includes [(8R,9S, 13S,14S,17S)-13-methyl-17-phosphonooxy-6,7,8,9, l 1,12, 14,15, 16,17- decahydrocyclopenta[a]phenanthren-3-yl] N,N-bis(2-chloroethyl)carbamate);
[0159] leuprolide (including pharmaceutically acceptable salts thereof, including leuprolide acetate. Leuprolide includes leuprorelin, Lupron (including Lupron injection and Lupron depot), Viadur, Eligard, and Leupromer. Leuprolide includes 5-oxo-L-prolyl-L- histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-Lprolinamide acetate);
[0160] triptorelin (including pharmaceutically acceptable salts thereof, including triptorelin acetate and triptorelin pamoate. Triptorelin includes Trelstar, Decapeptyl, Diphereline, Gonapeptyl, and Variopeptyl. Triptorelin includes 5-oxo-D-prolyl-L-histidyl-L- tryptophyl-L-seryl-L-tyrosyl-3-(lH-indol-2-yl)-L-alanylleucyl-L-arginyl-L- prolylglycinamide);
[0161] goserelin (including pharmaceutically acceptable salts thereof, including goserelin acetate. Goserelin includes Zoladex. Goserelin includes N-(21-((lH-indol-3- yl)methyl)- 1 , 1 -diamino- 12-(tert-butoxymethyl)-6-(2-(2- carbamoylhydrazinecarbonyl)cyclopentanecarbonyl)-15-(4-hydroxybenzyl)-18- (hydroxymethyl)-25-(lH-imidazol-5-yl)-9-isobutyl-8,l l, 14,17,20,23-hexaoxo- 2,7,10, 13,16, 19,22-heptaazapentacos- 1 -en-24-yl)-5-oxopyrrolidine-2-carboxamide);
[0162] histrelin (including pharmaceutically acceptable salts thereof, including histrelin acetate. Histrelin includes Vantas and Supprelin LA. Histrelin includes 5-oxo-L- prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-l-benzyl-D-histidyl-L-leucyl-N5- (diaminomethylene)-L-ornithyl-N-ethyl-L-prolinamide);
[0163] buserelin (including pharmaceutically acceptable salts thereof, including buserelin acetate. Beserelin includes Bigonist, SUPRADOPIN®, SURFACT®, Profact, Etilamide, and Tiloryth. Buserelin includes (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)- l-[[(2S)-l-[[(2S)-5-(diaminomethylideneamino)-l-[(2S)-2-(ethylcarbamoyl)pyrrolidin-l-yl]- l-oxopentan-2-yl]amino]-4-methyl-l-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]- l-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-l-oxopropan-2-yl]amino]-3-hydroxy-l- oxopropan-2-yl]amino]-3-(lH-indol-3-yl)-l-oxopropan-2-yl]amino]-3-(lH-imidazol-5-yl)-l- oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide);
[0164] abarelix (including pharmaceutically acceptable salts thereof, including acetyl-D-P-naphthylalanyl-D-4-chlorophenylalanyl-D-3-pyridylalanyl-L-seryl-L-N-methyl- tyrosyl-D-asparagyl-L-leucyl-L-N(8)-isopropyl-lysyl-L-prolyl-D-alanyl-amide. Abarelix can include Plenaxis™); or [0165] degarelix (including pharmaceutically acceptable salts thereof, including degarelix acetate. Degarelix includes FIRMAGON® (including FIRMAGON® injection). Degarelix includes D-alaninamide, N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-D- phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-4-[[[(4S)-hexahydro-2,6-dioxo- 4pyrimidinyl]carbonyl]amino]-L-phenylalanyl-4-[(aminocarbonyl)amino]-D-phenylalanyl- L-leucyl-N6-(l-methylethyl)-L-lysyl-L-prolyl);
[0166] or derivatives, salts, or analogues thereof, or any combination thereof. Any one or more of the aforementioned ADT compounds may be provided before, after, and/or simultaneous with administration of a compound of Formula (I) to a subject that has cancer, such as bladder cancer or prostate cancer so as to treat, inhibit, or ameliorate said cancer.
[0167] Anti-estrogen therapies may include therapies for a disease or condition in which the level of estrogen hormones in a patient are reduced, typically by surgical or pharmaceutical methods. Surgical methods of anti-ER therapy can comprise surgical ovariectomy (removal of the ovary or ovaries).
[0168] Pharmaceutical anti-ER therapies may comprise:
[0169] tamoxifen (including pharmaceutically acceptable salts thereof. Tamoxifen includes Nolvadex, Genox, Tamifen and (Z)-2-[4-(l,2-diphenylbut-l- enyl)phenoxy]-N,N-dimethylethanamine);
[0170] clomifene (or pharmaceutically acceptable salts thereof. Clomifene includes Clomid and (E,Z)-2-(4-(2-chloro-l,2-diphenylethenyl) phenoxy)-N,N-diethyl-ethanamine);
[0171] ormeloxifene (including pharmaceutically acceptable salts thereof. Ormeloxifene includes centchroman, Centron, Novex-DS, Saheli, Sevista, and l-[2-[4- [(3S,4R)-7-Methoxy-2,2-dimethyl-3-phenyl-chroman-4-yl]phenoxy]ethyl]pyrrolidine);
[0172] toremifene (including pharmaceutically acceptable salts thereof, including toremifene acetate. Toremifene includes 2-{4-[(lZ)-4-chloro-l,2-diphenyl-but-l-en-l- yl]phenoxy}-N,N-dimethylethanamine);
[0173] lasofoxifene (including pharmaceutically acceptable salts thereof. Lasofoxifene includes Fablyn and (5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-l-ylethoxy)phenyl]- 5,6,7,8-tetrahydronaphthalen-2-ol); [0174] ospemifene (including pharmaceutically acceptable salts thereof. Ospemifene includes Osphena and 2-(p-((Z)-4-Chloro-l,2-diphenyl-l- butenyl)phenoxy)ethanol);
[0175] raloxifene (including pharmaceutically acceptable salts thereof. Raloxifene includes Evista and [6-hydroxy-2-(4-hydroxyphenyl)- benzothiophen-3-yl]- [4- [2-(l -piped dyl)ethoxy]phenyl] -methanone);
[0176] fulvestrant (including pharmaceutically acceptable salts thereof. Fulvestrant includes Faslodex and (7α,17β)-7-{9-[(4,4,5,5,5- pentafluoropentyl)sulfinyl]nonyl}estra-l,3,5(10)-triene-3,17-diol);
[0177] brilanestrant (including pharmaceutically acceptable salts thereof. Brilanestrant includes (2E)-3-{4-[(lE)-2-(2-chloro-4-fluorophenyl)-l-(lH-indazol-5-yl)but- 1 -en- 1 -yljphenyl }prop-2-enoic acid);
[0178] elacestrant (including pharmaceutically acceptable salts thereof. Elacestrant includes (6R)-6-{2-[Ethyl({4-[2-(ethylamino)ethyl]phenyl}methyl)amino]-4- methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-ol);
[0179] anastrozole (including pharmaceutically acceptable salts thereof. Anastrozole includes Arimidex and 2,2'-[5-(lH-l,2,4-triazol-l-ylmethyl)-l,3- phenylene]bis(2-methylpropanenitrile));
[0180] letrozole (including pharmaceutically acceptable salts thereof. Letrozole includes Femara and 4,4'-((lH-l,2,4-triazol-l-yl)methylene)dibenzonitrile);
[0181] testolactone (including pharmaceutically acceptable salts thereof. Testolactone includes Teslac and (4a,S',4bR,10aR, 10b)S',12a)S)-10a, 12a-Dimethyl- 3,4,4a,5,6, 10a, 10b,l l, 12,12a-decahydro-2H-naphtho[2,l-f]chromene-2,8(4bH)-dione); or
[0182] exemestane (including pharmaceutically acceptable salts thereof. Exemestane includes Aromasin and 6-Methylideneandrosta-l,4-diene-3,17-dione);
[0183] or derivatives, salts, or analogues thereof, or any combination thereof.
[0184] Biologies include chemical or biochemical compounds produced by a living organism provided as a composition or as part of a therapy regimen. Biologic therapies can comprise: [0185] Bacillus Calmette-Guerin (BCG) vaccine (a standard of care treatment for patients with bladder cancer. BCG vaccine includes biosimilar agents or strains that are used for the treatment of bladder cancer, including non-muscle invasive bladder cancer);
[0186] Sargramostim (Sargramostim includes Leukine, and biosimilars);
[0187] Filgrastim (Filgrastim includes Neupogen, Zarxio, and biosimilars, and the pegylated formulations thereof, including pegfilgrastim);
[0188] recombinant interleukin-12 (including analogues, derivatives, and biosimilars thereof); or
[0189] interferon alpha (including analogues, derivatives, and biosimilars thereof);
[0190] or a combination thereof. Any one or more of the aforementioned biologic treatments may be administered before, after, and/or simultaneous with administration of a compound of Formula (I) so as to treat, inhibit, or ameliorate cancer, such as bladder cancer or prostate cancer.
[0191] As used herein, the term "virus-based therapy" refers to the use of virus or virus like particles for use in the treatment or inhibition of a disease or condition. In some embodiments, a virus-based therapy may comprise a viral carrier, comprising use of a reovirus, bunyavirus, flavivirus, rubivirus, filovirus, arenavirus, arterivirus, or calicivirus. In some embodiments, a virus-based therapy may comprise a retrovirus, an adenoviral vector, (including the oncolytic adenovirus vector CG0070 (Cold Genesys)), or a Coxsackievirus A21 (CVA21; CAVATAK, Viralytics), or any combination thereof.
[0192] As used herein the term "chemotherapy" refers to any therapy that comprises natural or synthetic chemotherapeutic agents now known or to be developed in the medical arts. Examples of chemotherapeutic agents comprise the numerous cancer drugs that are currently available. However, chemotherapy also comprises any drug, natural or synthetic, that is intended to treat or inhibit a disease state. In certain embodiments, chemotherapy may comprise the administration of several state of the art drugs intended to treat or inhibit the disease state. In some embodiments, a chemotherapy comprises gemcitabine, cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, mustine, vincristine, procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, etoposide, epirubicin, capecitabine, methotrexate, folinic acid, lenalidomide, pemetrexed, azacitidine and analog decitabine, mitomycin C, apaziquone, eribulin, valrubicin, vinflunine, pirarubicine, pralatrexate, temsirolimus, sirolimus, ifosfamide, irinotecan, rubitecan, or AZD4877, or analogues, derivatives, and any combination thereof. In some embodiments, the chemotherapeutic agent or chemotherapy is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
[0193] In some embodiments, the chemotherapy is a taxane-based chemotherapy agent or a platinum-based antineoplastic agent. Taxanes are a class of diterpenoid drugs that have anti-tumor activity against a wide range of human cancers. Paclitaxel was originally isolated from the bark of the Yew tree, and was known to act by interfering with the normal function of microtubule breakdown. Paclitaxel binds to the β subunit of tubulin, the building blocks of microtubules, causing hyper-stabilization of the microtubule structures. The resulting paclitaxel/microtubule structure is unable to disassemble, thereby arresting mitosis and inhibiting angiogenesis. Platinum-based antineoplastic agents are a class of platinum containing agents for use in cancer therapy. Platinum-based antineoplastic agents inhibit DNA repair and/or DNA synthesis in cells, including cancer cells.
[0194] A taxane-based chemotherapy agent may comprise one or more of the following agents, or other taxane-based chemotherapy agents now known or to be developed in the medical arts:
[0195] docetaxel (including pharmaceutically acceptable salts thereof. Docetaxel may include l,7p, 10P-trihydroxy-9-oxo-5p,20-epoxytax-l l-ene-2a,4,13a-triyl 4-acetate 2- benzoate 13-{(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate}, Taxotere, or Docecad);
[0196] paclitaxel ((including pharmaceutically acceptable salts thereof. Paclitaxel may include (2α,4α,5β,7β, 10β, 13 α)-4, 10-Bis(acetyloxy)- 13 -{ [(2R,3 S)-3 -(benzoylamino)-2- hydroxy-3-phenylpropanoyl]oxy}-l,7-dihydroxy-9-oxo-5,20-epoxytax-l l-en-2-yl benzoate, Taxol, PTX);;
[0197] cabazitaxel (including pharmaceutically acceptable salts thereof. Cabazitaxel may include (l S,2S,3R,4S,7R,9S, 10S, 12R, 15S)-4-(Acetyloxy)-15-{[(2R,3S)-3- { [(tert-butoxy)carbonyl]amino } -2-hy droxy-3 -phenylpropanoyl] oxy } - 1 -hy droxy-9, 12- dimethoxy-10,14, 17,17-tetramethyl-l l-oxo-6 oxatetracyclo[l 1.3.1.03,10.04,7]heptadec-13- en-2-yl benzoate, XRP-6258, Jevtana). Cabazitaxel in combination with prednisone may be a treatment option for hormone-refractory prostate cancer following docetaxel-based treatment;
[0198] larotaxel (including pharmaceutically acceptable salts thereof. Larotaxel may include (2α,5β,7β, 10β, 13 α)-4, 10-Diacetoxy- 1 -hydroxy- 13 - { [(2R,3 S)-2-hydroxy-3 - ({[(2-methyl-2-propanyl)oxy]carbonyl}amino)-3-phenylpropanoyl]oxy}-9-oxo-5,20-epoxy- 7, 19-cyclotax-l l-en-2-yl benzoate, XRP9881, RPR109881);
[0199] ortataxel (including pharmaceutically acceptable salts thereof. Ortataxel may include (3aS,4R,7R,8aS,9S, 10aR,12aS, 13S, 13aS)-7, 12a-bis(acetyloxy)-4-({(2R,3S)-3- [tert-butoxycarbonyl)amino]-2-hydroxy-5-methylhexanoyl}oxy)-9-hydroxy-5, 8a, 14, 14- tetramethyl-2,8-dioxo-3a,4,7,8,8a,9, 10,10a,12, 12a, 12b,13-dodecahydro-6, 13a- methano[ 1 ,3 ]dioxolo[8,9]cyclodeca[ 1 ,2-d] [ 1 ]benzoxet- 13 -yl benzoate);
[0200] milataxel (including pharmaceutically acceptable salts thereof. Milataxel may include (2a,5p,7p, 10p, 13a)-4-Acetoxy-13-{[(2R,3R)-3-(2-furyl)-2-hydroxy-3-({[(2- methyl-2-propanyl)oxy]carbonyl}amino)propanoyl]oxy}-l,10-dihydroxy-9-oxo-7- (propionyloxy)-5,20-epoxytax-l l-en-2-yl benzoate, MAC-321, TL-139);
[0201] tesetaxel (including pharmaceutically acceptable salts thereof. Tesetaxel may include (2aS,2bR,3S,4S,6S,8aR, 10S,l laS, l lbR, 13aR)-2a-(acetyloxy)-6-{[(2R,3S)-3- [(tert-butoxycarbonyl)amino]-3-(3-fluoropyridin-2-yl)-2-hydroxypropanoyl]oxy}-10- [(dimethylamino)methyl]-4-hydroxy-7, 1 lb, 14, 14-tetramethyl- 2a,2b,3,4,5,6,8a,l la, l lb,12, 13,13a-dodecahydro-2H-4,8- methano[l,3]dioxolo[3,4]cyclodeca[l,2-d][l]benzoxet-3-yl benzoate, DJ-927); or
[0202] abraxane (including pharmaceutically acceptable salts thereof. Abraxane is a protein bound formulation of paclitaxel, also known as nanoparticle albumin-bound paclitaxel or nab-paclitaxel);
[0203] or combinations, analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof.
[0204] In some embodiments, the chemotherapy is an antineoplastic agent, such as a platinum-based antineoplastic, optionally, wherein the antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy. An antineoplastic agent may include, for example, nucleoside analogues, antifolates, antimetabolites, enzyme inhibitors such as topoisomerase I inhibitors, anthracyclines, podophyllotoxins, alkaloids, alkylating agents, platinum compounds, antibodies, tyrosine kinase inhibitors, mTOR inhibitors, retinoids, immunomodulatory agents, histone deacetylase inhibitors. Thus, an antineoplastic agent may include, for example, afatinib, aflibercept, alemtuzumab, alitretinoin, altretamine, anagrelide, arsenic trioxide, asparaginase, axitinib, azacitidine, BCG vaccine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, capecitabine, carboplatin, carmofur, carmustine, cetuximab, chlorambucil, chlormethine, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dasatinib, daunorubicin, decitabine, denileukin diftitox, denosumab, docetaxel, doxorubicin, epirubicin, erlotinib, estramustine, etoposide, everolimus, floxuridine, fludarabine, fluorouracil, fotemustine, gefitinib, gemcitabine, gemtuzumab ozogamicin, hydroxycarbamide, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, ipilimumab, irinotecan, isotretinoin, ixabepilone, lapatinib, lenalidomide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, nedaplatin, nelarabine, nilotinib, nivolumab, ofatumumab, oxaliplatin, paclitaxel, panitumumab, panobinostat, pazopanib, pembrolizumab, pemetrexed, penostatin, pertuzumab, pomalidomide, ponatinib, procarbazine, raltitrexed, regorafenib, ritixumab, romidepsin, ruxolitinib, sorafenib, streptozotocin, sunitinib, tamibarotene, tegafur, temozolomide, temsirolimus, teniposide, thalidomide, tioguanine, topotecan, tositumomab, trastuzumab, tretinoin, valproate, valrubicin, vandetanib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vemurafenib, or vorinostat. A platinum-based antineoplastic may comprise one or more of the following agents or a platinum-based antineoplastic now known or to be developed in the medical arts.
[0205] cisplatin (including pharmaceutically acceptable salts thereof. Cisplatin may include (SP-4-2)-diamminedichloroplatinum(II) or Platinol);
[0206] carboplatin (including pharmaceutically acceptable salts thereof. Carboplatin may include Paraplatin or cis-diammine(cyclobutane-l, l-dicarboxylate- 0,0')platinum(II)); [0207] dicycloplatin (including pharmaceutically acceptable salts thereof. Dicycloplatin may include DCP, and may be derived from carboplatin and 1,1-cyclobutane dicarboxylates);
[0208] oxaliplatin (including pharmaceutically acceptable salts thereof. Oxaliplatin may include Eloxatin or [(lR,2R)-cyclohexane-l,2-diamine](ethanedioato- 0,0')platinum(II));
[0209] nedaplatin (including pharmaceutically acceptable salts thereof. Nedaplatin may include Aqupla or Diammine[(hydroxy-KO)acetato(2-)-KO]platinum);
[0210] triplatin tetranitrate (including pharmaceutically acceptable salts thereof. Triplatin tetranitrate may include BBR3464 or Ci2H54Cl2Ni40i2Pt3);
[0211] phenanthriplatin (including pharmaceutically acceptable salts thereof. Phenanthriplatin may include cis-[Pt(NH3)2-(phenanthridine)Cl]N03);
[0212] picoplatin (including pharmaceutically acceptable salts thereof. Picoplatin may include azane-2-methylpyridine-platinum(2+)-dichloride);
[0213] pyriplatin (including pharmaceutically acceptable salts thereof. Pyriplatin may include cis-diammine(pyridine)chloroplatinum(II) or cDPCP); or
[0214] ormaplatin (including pharmaceutically acceptable salts thereof. Ormaplatin may include tetraplatin or tetrachloro(l,2-cyclohexanediamine-N,N')-,(OC-6-22- (trans))platinum); or
[0215] satraplatin (including pharmaceutically acceptable salts thereof. Satraplatin may include JM216 or (OC-6-43)- bis(acetato)amminedichloro(cyclohexylamine)platinum);
[0216] or analogues or derivatives or any combinations thereof.
[0217] As used herein, the term "radiation therapy" (also known as radiation oncology or radiotherapy) refers to the medical use of ionizing radiation as part of a cancer treatment regimen to kill malignant cells that are progressing through the cell cycle (e.g., in any phase of the cell cycle). The radiation therapy may be internal or external radiotherapy. External radiotherapy involves targeting doses (or "fractions") of high-energy beams of radiation, either X-rays or gamma rays, to the tumor. Internal radiotherapy involves positioning the source of radioactivity inside the body close to the tumor. This can be achieved in two ways: by brachytherapy or by radioisotope therapy. Brachytherapy involves placing a solid source of radiation next to a tumor to give a high dose of radiotherapy. Radioisotope therapy involves administration of a radioactive substance, a radioisotope, either as an intravenous injection, or as an oral capsule or liquid.
[0218] As used herein, the term "statin" refers to any of a class of lipid-lowering drugs that reduce serum cholesterol levels by inhibiting HMG-CoA reductase, a key enzyme involved in the biosynthesis of cholesterol, the mevalonate pathway or HMG-CoA reductase pathway. Non-limiting examples include atorvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and/or simvastatin, or any combinations thereof, or a combination of a statin and another agent, such as ezetimibe/simvastatin.
[0219] As used herein, the term "repurposed drug therapy" refers to a strategy by which a new or additional value is generated from a drug by targeting a disease other than those diseases for which the drug was originally intended. In some embodiments, a repurposed drug therapy may comprise eflornithine, indinavir, metformin, or ritonavir, or a combination thereof.
[0220] As used herein, the term "small molecule inhibitor therapy" refers to small organic molecules, peptides, antibodies, cyclic peptides and peptidomimetics that are small molecules, such as less than 10,000 Daltons (but not zero), and that act by inhibition, now known or to be developed in the medical arts. In some embodiments, a small molecule inhibitor therapy may comprise:
[0221] alisertib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Alisertib includes MLN8237; 4-{[9-Chloro-7-(2-fluoro-6- methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid);
[0222] BGJ398 (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. BGJ398 is a fibroblast growth factor receptor (FGFR) inhibitor and includes infigratinib; 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-l-{6-[4-(4-ethyl-piperazin-l- yl)-phenylamino]-pyrimidin-4-yl } - 1 -methyl-urea);
[0223] BAY1 163877 (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. BAY1163877 is a FGFR inhibitor and includes rogaratinib; 4-((4-amino-5-(7-methoxy-5-methylbenzo[b]thiophen-2-yl)-6- (methoxymethyl)pyrrolo[2,l-f][l,2,4]triazin-7-yl)methyl)piperazin-2-one); [0224] belinostat (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Belinostat includes BELEODAQ, PXD101; (2E)- N-Hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide);
[0225] bortezomib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Bortezomib includes VELCADE, NEOMIB, BORTEC AD ; [( 1 R)-3 -methyl- 1 -( { (2 S)-3 -phenyl-2- [(pyrazin-2- ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid);
[0226] bosutinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Bosutinib includes BOSULIF; 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-l-yl)propoxy]quinoline-3- carbonitrile);
[0227] cabozantinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Cabozantinib includes CABMETYX, COMITRIQ; N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1, 1- dicarboxamide);
[0228] copanlisib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Copanlisib includes BAY 80-6946; 2-Amino-N- [7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2-c]quinazolin-5- yl]pyrimidine-5-carboxamide);
[0229] crizotinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Crizotinib includes XALKORI; 3-[(lR)-l-(2,6- dichloro-3-fluorophenyl)ethoxy]-5-(l-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine);
[0230] dasatinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Dasatinib includes BMS-354825, SPRYCEL; N- (2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4- pyrimidinyl]amino]-5-thiazole carboxamide monohydrate);
[0231] dovitinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Dovitinib includes TKI258; (3Z)-4-amino-5- fluoro-3-[5-(4-methylpiperazin-l-yl)-l,3-dihydrobenzimidazol-2-ylidene]quinolin-2-one); [0232] entinostat (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Entinostat includes SNDX-275, MS-275; Pyridin-
3- ylmethyl N-[[4-[(2-aminophenyl)carbamoyl]phenyl]methyl]carbamate);
[0233] erlotinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Erlotinib includes TARCEVA; N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine);
[0234] everolimus (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Everolimus includes RADOOl, 42-0-(2- hydroxyethyl)rapamycin; Dihydroxy-12-[(2R)-l-[(l S,3R,4R)-4-(2-hydroxyethoxy)-3- methoxycyclohexyl]propan-2-yl]- 19,30-dimethoxy- 15, 17,21 ,23 ,29,35-hexam ethyl- 11,36- dioxa-4-azatricyclo[30.3.1.0 hexatriaconta-16,24,26,28-tetraene-2,3, 10,14,20-penton]);
[0235] gefitinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Gefitinib includes ZD 1839, IRES S A; N-(3-chloro-
4- fluoro-phenyl)-7-methoxy-6-(3-mo holin-4-ylpropoxy)quinazolin-4-amine);
[0236] imatinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Imatinib includes GLEEVEC, GLIVEC, STI-571; 4-[(4- methylpiperazin-l-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2- y 1 ] amino } pheny l)b enzami de) ;
[0237] ixazomib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Ixazomib includes NINLARO, MLN2238; N2- (2,5-Dichlorobenzoyl)-N-[(lR)-l-(dihydroxyboryl)-3-methylbutyl]glycinamide);
[0238] lapatinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Lapatinib includes lapatinib ditosylate, TYKERB, T YVERB ; N- [3 -Chloro-4- [(3 -fluorophenyl)methoxy ]phenyl] -6-
[5-[(2-methylsulfonylethylamino)methyl]-2-furyl] quinazolin-4-amine);
[0239] lonafarnib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Lonafarnib includes SARAS AR, SCH 66336; 4- (2-{4-[(l lR)-3, 10-dibromo-8-chloro-6,l l-dihydro-5H-benzo[5,6]cyclohepta[l,2-b]pyridin- 11 -yl]piperidin- 1 -yl } -2-oxoethyl)piperidine- 1 -carboxamide);
[0240] merestinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Merestinib includes LY2801653; N-(3-Fluoro-4- {[l-methyl-6-(lH-pyrazol-4-yl)-lH-indazol-5-yl]oxy}phenyl)-l-(4-fluorophenyl)-6-methyl- 2-oxo-l,2-dihydropyridine-3-carboxamide);
[0241] MLN8054 (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. 4-[[9-chloro-7-(2,6-difluorophenyl)-5H- pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid);
[0242] olaparib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Olaparib includes AZD-2281, LY PARZA; 4-[(3-[(4- cyclopropylcarbonyl)piperazin-l-yl]carbonyl) -4-fluorophenyl]methyl(2H)phthalazin-l-one);
[0243] palbociclib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Palbociclib includes PD-0332991, IBRANCE; 6- Acetyl-8-cyclopentyl-5-methyl-2-{[5-(l-piperazinyl)-2-pyridinyl]amino}pyrido[2,3- d]pyrimidin-7(8H)-one);
[0244] pazopanib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Pazopanib includes VOTRIENT; 5-({4-[(2,3- Dimethyl-2H-indazol-6-yl)methylamino]pyrimidin-2-yl}amino)-2- methy lb enzene sulf onami de) ;
[0245] pexidartinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Pexidartinib includes PLX-3397; 5-[(5-Chloro-lH- pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-{[6-(trifluoromethyl)-3-pyridinyl]methyl}-2- pyridinamine);
[0246] rapamycin (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Rapamycin includes sirolimus, RAPAMUNE; (1R, 9S, 12S, 15R, 16E, 18R,19R,21R,23S,24E,26E,28E,
30S,32S,35R)-l, 18-dihydroxy-12-{(2R)-l-[(l S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-2- propanyl } - 19,30-dimethoxy- 15,17,21 ,23 ,29,35-hexamethyl- 11 ,36-dioxa-4- azatricyclo[30.3.1.0~4,9~]hexatriaconta-16,24,26,28-tetraene-2,3, 10,14,20-pentone);
[0247] sapanisertib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. 5-(4-Amino-l-propan-2-ylpyrazolo[3,4- d]pyrimidin-3-yl)-l,3-benzoxazol-2-amine);
[0248] sorafenib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Sorafenib includes sorafenib tosylate, NEXAVAR; 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2- carboxamide);
[0249] sunitinib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Sunitinib includes SU11248, SUTENT; N-(2- diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-lH-indol-3-ylidene)methyl]-2,4-dimethyl-lH- py rrol e-3 -carb oxami de);
[0250] tipifarnib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Tipifarnib includes Rl 15777, ZARNESTRA; (+)- 6-[(R)-Amino-(4-chlorophenyl)-(3-methylimidazol-4-yl)methyl]-4-(3-chlorophenyl)-l- methylquinolin-2-one);
[0251] vandetanib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Vandetanib includes CAPRELSA, ZD6474; N-(4- bromo-2-fluorophenyl)-6-methoxy-7-[(l-methylpiperidin-4-yl)methoxy]quinazolin-4- amine);
[0252] vistusertib (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Vistusertib includes AZD2014; 3-[2,4-Bis((3S)-3- methylmorpholin-4-yl)pyrido[5,6-e]pyrimidin-7-yl]-N-methylbenzamide); or
[0253] vorinostat (including analogues, derivatives, and including pharmaceutically acceptable salts thereof. Vorinostat includes suberanilohydroxamic acid, ZOLINZA; N-Hydroxy-N'-phenyloctanediamide);
[0254] or any combinations thereof.
[0255] As used herein, the term "therapeutic antibody therapy" refers to any antibody, now known or to be developed in the medical arts, which can be administered to a subject as an active agent, including derivatives and fragments thereof, or antigen-specific ligand molecules, such as antibody Fab fragments, or antibody Fc fragments, synthetic receptors, soluble receptors, that selectively bind a target antigen. In some embodiments, a therapeutic antibody therapy may comprise cetuximab, ritixumab, bevacizumab, ranibizumab, trastuzumab, or panitumumab, fragments thereof, or a combination thereof.
[0256] As used herein, the term "immunotherapy" refers to a therapy for a disease that relies on an immune response. In some embodiments, an immunotherapy may comprise nivolumab, durvalumab, pembrolizumab, atezolizumab, ipilimumab, tremelimumab, CA- 170, EO-PV-01, or a tumor cell-derived vaccine therapy, or any combinations thereof.
[0257] In some embodiments, a compound of Formula (I) may be administered alone or in combination with a therapy as described herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic treatments, virus-based therapies, surgeries, chemotherapies, such as a taxane-based chemotherapy agent, an antineoplastic agent, such as a platinum-based antineoplastic agent, radiation therapies, statin treatments, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combination thereof to a subject in need. In some embodiments, the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
[0258] In some embodiments, a medicament for the treatment or inhibition of cancer, such as bladder cancer or prostate cancer, may be prepared by providing a compound of Formula (I) in a composition. In some embodiments, a medicament for the treatment or inhibition of cancer, such as bladder cancer or prostate cancer, may be prepared by providing a compound of Formula (I) in combination with one or more of the therapies described herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic treatments, virus-based therapies, surgeries, chemotherapies, such as a taxane-based chemotherapy agent, an antineoplastic agent, such as a platinum-based antineoplastic agent, radiation therapies, statin treatments, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
[0259] In some embodiments, a product combination comprising a compound of Formula (I) in combination with a one or more of the therapies as described herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic treatments, virus-based therapies, surgeries, chemotherapies, such as a taxane-based chemotherapy agent, an antineoplastic agent, such as a platinum-based antineoplastic agent, radiation therapies, statin treatments, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy may be provided or administered to a subject in need.
[0260] The compositions described herein may be formulated for oral, intranasal, or parenteral administration. Oral administration may include formulation of the compositions for administration to the oral cavity, including for administration to the digestive tract, the buccal lining, or the respiratory tract through the oral cavity, for example, formulation of the compositions as a tablet, pill, capsule, pellet, dragee, gummy, powder, softgel, liquid, syrup, suspension, solution, or inhalable composition. Intranasal administration may include formulation for administration by the nasal cavity, and may include drops, spray, insufflation, or inhalable compositions. Parenteral administration may include, for example, intraperitoneal, infusion, intramuscular, subcutaneous, intradermal, or intravenous injection.
[0261] In some embodiments, the compositions described herein further include pharmaceutically acceptable carriers and excipients, depending on the desired delivery or mode of administration format.
A. Exemplary pharmaceutically acceptable carriers
[0262] In some embodiments, the pharmaceutically acceptable carrier may comprise glycerol. In some embodiments, the pharmaceutically acceptable carrier may comprise a mixture of triacylglycerols, monoacylglycerols, diacylglycerols, and/or free fatty acids. In some embodiments, the pharmaceutically acceptable carrier may comprise a mixture of triacylglycerols. In some embodiments, the pharmaceutically acceptable carrier may comprise a mixture of long chain (Cs-Cso) saturated or unsaturated fatty acids, fatty alcohols, or glyceryl esters of one or more fatty acids. In some embodiments, the long chain saturated or unsaturated fatty acids may comprise from 10 to 40 carbon atoms (C10-C40). In some embodiments, the long chain saturated or unsaturated fatty acids may comprise from 10 to 20 carbon atoms (C10-C20). The mixture of triacylglycerols, monoacylglycerols, diacylglycerols, and/or free fatty acids can be an oil or wax at room temperature. [0263] In some embodiments, each long chain saturated or unsaturated fatty acid is selected from caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linolenic acid (including alpha-linolenic acid and/or gamma- linolenic acid), linoleic acid, arachidic acid, ricinoleic acid, dihydroxystearic acid, behenic acid, ligoceric acid, erucic acid, and/or godonic acid. In some embodiments, each long chain saturated or unsaturated fatty acid is selected from (Z)-9-octadecenoic acid, oleic acid (8CI), 9-cis-octadecenoic acid, 9Z-octadecenoic acid, B 115, Clear FRAC EF, Crodacid O-P, Crossential O 94, D 100, D 100 (fatty acid), Edenor ΑΤΪ05, Edenor FTi05, Emersol 205, Emersol 211, Emersol 213 F, Emersol 214 F, Emersol 233, Emersol 6313 F, Extra Oleic 80R, Extra Oleic 90, Extra Oleic 99, Extra Olein 80, Extra Olein 90, Extra Olein 90R, Extra Olein A 1981, Industrene 105, Lunac O-CA, Lunac O-LL, Lunac O-P, Lunac O-V, Lunac OA, NAA 35, NAA 38, Neo-Fat 92-04, Oleine 7503, Pamolyn 100, Priolene 6204, Priolene 6906, Priolene 6907, Priolene 6928, Priolene 6930, Priolene 6933, Vopcolene 27, Wecoline OO, and/or cis-oleic acid.
[0264] In some embodiments, the pharmaceutically acceptable carrier may comprise a mixture of triacylglycerols having long chain saturated or unsaturated fatty acids including alpha-linolenic acid, arachidic acid, behenic acid, capric acid, caproic acid, caprylic acid, dihydroxystearic acid, erucic acid, gondonic acid, lauric acid, lignoceric acid, linoleic acid, myristic acid, oleic acid, palmitic acid, palmitoleic acid, ricinoleic acid, and/or stearic acid. In some embodiments, the pharmaceutically acceptable carrier may comprise a mixture of triacylglycerols obtained from the seeds of Ricinus communis L., Euphorbiaceae; Gossypium herbaceum L., Malvaceae; Vitis vinifera L., Vitaceae; Arachis hypogaea L., Leguminosae; Brassica napus L., Brassicaceae; Brassica rapa L., Brassicaceae; Brassica juncea L., Brassicaceae; Helianthus annuus L., Compositae; Carthamus tinctorius L., Compositae; Sesamum indicum L., Pedaliaceae; or Glycine max L., Fabaceae; or obtained from the kernels of Cocos nucifera L., Palmae; or obtained from the grain of Zea mays L., Gramineae; or obtained from the fruit of Olea europaea L, Oleaceae; Elaeis guineensis, Arecaceae; Elaeis oleifera, Arecaceae; or Attalea maripa, Arecaceae, or any combinations thereof. In some embodiments, pharmaceutically acceptable carrier may comprise a mixture of triacylglycerols, where the mixture of triacylglycerols have a fatty acid content comprising 44-75% linoleic acid, 14-35% oleic acid, 3-10% palmitic acid, 1-8% stearic acid, 0.6-4% arachidic acid, and 1% behenic acid.
[0265] In some embodiments, the pharmaceutically acceptable carrier may comprise an oil selected from castor oil, coconut oil, corn oil, cottonseed oil, grapeseed oil, olive oil, palm oil, peanut oil, rapeseed oil, canola oil, safflower oil, sesame oil, soybean oil, or sunflower oil, or any combinations thereof.
[0266] In some embodiments, the pharmaceutically acceptable carrier may comprises a mixture of triacylglycerols and further comprise dimethyl sulfoxide. Dimethyl sulfoxide may be used as a pharmaceutically acceptable carrier to facilitate the uptake of a compound of Formula (I), alone or in combination with an additional therapy as described herein, into cells or tissues of a subject. Dimethyl sulfoxide may be used as a pharmaceutically acceptable carrier to facilitate absorption of a compound of Formula (I) in the gastrointestinal tract of a subject.
[0267] In some embodiments, the pharmaceutically acceptable carrier may comprise propylene glycol. In some embodiments, the pharmaceutically acceptable carrier may comprise esters of propylene glycol. In some embodiments, the ester of propylene glycol can be propylene glycol monocaproate, propylene glycol monocaprylate, propylene glycol monodecanoate, propylene glycol monolaurate, propylene glycol monomyri state, propylene glycol monopalmitate, propyleneglycol monostearate, propylene glycol monooleate, propylene glycol monolinolenate, propylene glycol dicaproate, propylene glycol dicaprylate, propylene glycol didecanoate, propylene glycol dilaurate, propylene glycol dimyristate, propylene glycol dipalmitate, propyleneglycol distearate, propylene glycol dioleate, or propylene glycol dilinolenate, or any combinations thereof. In some embodiments, the pharmaceutically acceptable carrier may comprise propylene carbonate. In some embodiments, the pharmaceutically acceptable carrier may comprise Capryol™ 90, which is propylene glycol monocaprylate.
[0268] In some embodiments, the pharmaceutically acceptable carrier may comprise esters of polyethylene glycol. In some embodiments, the ester of polyethylene glycol can comprise PEG-8, PEG-10, PEG-25, PEG-55, PEG 75, PEG 120, or PEG 660 monocaproate or dicaproate; PEG-8, PEG-10, PEG-25, PEG-55, PEG 75, PEG 120, or PEG 660 monocaprylate or dicaprylate; PEG-8, PEG-10, PEG-25, PEG-55, PEG 75, PEG 120, or PEG 660 monodecanoate or didecanoate; PEG-8, PEG-10, PEG-25, PEG-55, PEG 75, PEG 120, or PEG 660 monolaurate or dilaurate; PEG-8, PEG-10, PEG-25, PEG-55, PEG 75, PEG 120, or PEG 660 monomyristate or dimyristate; PEG-8, PEG-10, PEG-25, PEG-55, PEG 75, PEG 120, or PEG 660 monopalmitate or dipalmitate; PEG-8, PEG-10, PEG-25, PEG-55, PEG 75, PEG 120, or PEG 660 monostearate or distearate; PEG-8, PEG-10, PEG-25, PEG- 55, PEG 75, PEG 120, or PEG 660 monooleate or dioleate; PEG-8, PEG-10, PEG-25, PEG- 55, PEG 75, PEG 120, or PEG 660 monolinolenate or dilinolenate; or any combination thereof. In some embodiments, the pharmaceutically acceptable carrier may comprise diethylene glycol monoethyl ether.
[0269] In some embodiments, the pharmaceutically acceptable carrier may comprises a pegylated glyceride. Exemplary pegylated glycerides comprise GELUCIRE® 44/14 (lauroyl macrogol-32 glycerides) and/or GELUCIRE® 50/13 (stearoyl macrogol-32 glycerides).
[0270] In some embodiments, the pharmaceutically acceptable carrier may comprises a fatty acid ester having the general formula Ri-C(=0)-0-R2, where Ri and R2 are each saturated or unsaturated Cs-Cso hydrocarbons optionally substituted with one or more hydroxyl groups. In some embodiments, each of Ri and R2 can be the same. In some embodiments, each of Ri and R2 can be different. In some embodiments, the fatty acid ester can be methyl caproate, ethyl caproate, propyl caproate, isopropyl caproate, butyl caproate, sec-butyl caproate, tert-butyl caproate, pentyl caproate, hexyl caproate, heptyl caproate, octyl caproate, nonyl caproate, or decyl caproate, or any combination thereof. In some embodiments, the fatty acid ester can be methyl caprylate, ethyl caprylate, propyl caprylate, isopropyl caprylate, butyl caprylate, sec-butyl caprylate, tert-butyl caprylate, pentyl caprylate, hexyl caprylate, heptyl caprylate, octyl caprylate, nonyl caprylate, or decyl caprylate, or any combination thereof. In some embodiments, the fatty acid ester can be methyl decanoate, ethyl decanoate, propyl decanoate, isopropyl decanoate, butyl decanoate, sec-butyl decanoate, tert-butyl decanoate, pentyl decanoate, hexyl decanoate, heptyl decanoate, octyl decanoate, nonyl decanoate, or decyl decanoate, or any combination thereof. In some embodiments, the fatty acid ester can be methyl laurate, ethyl laurate, propyl laurate, isopropyl laurate, butyl laurate, sec-butyl laurate, tert-butyl laurate, pentyl laurate, hexyl laurate, heptyl laurate, octyl laurate, nonyl laurate, or decyl laurate, or any combination thereof. In some embodiments, the fatty acid ester can be methyl myristate, ethyl myristate, propyl myristate, isopropyl myristate, butyl myristate, sec-butyl myristate, tert-butyl myristate, pentyl myristate, hexyl myristate, heptyl myristate, octyl myristate, nonyl myristate, or decyl myristate, or any combination thereof. In some embodiments, the fatty acid ester can be methyl palmitate, ethyl palmitate, propyl palmitate, isopropyl palmitate, butyl palmitate, sec-butyl palmitate, tert-butyl palmitate, pentyl palmitate, hexyl palmitate, heptyl palmitate, octyl palmitate, nonyl palmitate, or decyl palmitate, or any combination thereof. In some embodiments, the fatty acid ester can be methyl stearate, ethyl stearate, propyl stearate, isopropyl stearate, butyl stearate, sec-butyl stearate, tert-butyl stearate, pentyl stearate, hexyl stearate, heptyl stearate, octyl stearate, nonyl stearate, or decyl stearate, or any combination thereof. In some embodiments, the fatty acid ester can be methyl oleate, ethyl oleate, propyl oleate, isopropyl oleate, butyl oleate, sec-butyl oleate, tert-butyl oleate, pentyl oleate, hexyl oleate, heptyl oleate, octyl oleate, nonyl oleate, or decyl oleate, or any combination thereof. In some embodiments, the fatty acid ester can be methyl linolenate, ethyl linolenate, propyl linolenate, isopropyl linolenate, butyl linolenate, sec-butyl linolenate, tert-butyl linolenate, pentyl linolenate, hexyl linolenate, heptyl linolenate, octyl linolenate, nonyl linolenate, or decyl linolenate, or any combinations thereof.
[0271] In some embodiments, the pharmaceutically acceptable carrier may comprise a sorbitan ester. In some embodiments, the sorbitan ester can comprise sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, or sorbitan isostearate, or any combinations thereof. In some embodiments, the sorbitan ester can comprise Span 20, Span 40, Span 60, Span 80, Span 83, Span 85, Span 120, or any combination thereof.
[0272] In some embodiments, the pharmaceutically acceptable carrier may comprise a polysorbate. In some embodiments, the polysorbate can comprise polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene (4) sorbitan monopalmitate, or polyoxyethylene (4) sorbitan monostearate, or polyoxyethylene (4) sorbitan monooleate, or any combinations thereof. In some embodiments, the polysorbate can comprise Tween 20, Tween 21, Tween 40, Tween 60, Tween 61, Tween 65, or Tween 80, or any combination thereof.
[0273] In some embodiments, the concentration of a compound of Formula (I) dissolved or suspended in the at least one pharmaceutically acceptable carrier that comprises a mixture of triacylglycerols, monoacylglycerols, diacylglycerols, and/or free fatty acids may vary from about or any number in between 1-1000 mg of a compound of Formula (I) per mL of pharmaceutically acceptable carrier. In some embodiments, the concentration of a compound of Formula (I) ranges from 1, 2, 5, 7, 10, 12, 15, 17, 20, 22, 25, 27, 30, 32, 35, 37, 40, 42, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg/mL or within a range defined by any two of the aforementioned values.
[0274] In some embodiments, the concentration of a therapy agent that is used in combination with a compound of Formula (I) ranges from 1, 2, 5, 7, 10, 12, 15, 17, 20, 22, 25, 27, 30, 32, 35, 37, 40, 42, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg/mL or within a range defined by any two of the aforementioned values.
B. Excipients
[0275] Some embodiments disclosed herein include a pharmaceutical composition comprising a compound of Formula (I), at least one pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient. In some embodiments, the composition further comprises an additional therapy as described herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus- based therapies, surgeries, chemotherapies, antineoplastic therapies, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapy or antineoplastic therapy is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy. The at least one pharmaceutically acceptable excipient can be selected from a sugar, a starch, a cellulose preparation, silicon dioxide aerosol, gelatin, calcium phosphate dibasic, sodium lauryl sulfate, magnesium stearate, sodium stearyl fumarate, talc, polyethylene glycol, or polyvinylpyrrolidone, or any combinations thereof. In one embodiment, the at least one pharmaceutically acceptable excipient can be selected from a pregelatinized starch, partially pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, a lactose-cellulose blend, methyl cellulose, or silicon dioxide aerosol, or any combinations thereof. In one embodiment, the at least one pharmaceutically acceptable excipient can be selected from microcrystalline cellulose, lactose, sucrose, starch powder, maize starch or derivatives thereof, cellulose esters of alkanoic acids, cellulose alkyl esters, stearic acid, magnesium oxide, sodium and/or calcium salts of phosphoric and sulfuric acids, acacia gum, sodium alginate, or polyvinyl alcohol, or any combinations thereof. In one embodiment, the at least one pharmaceutically acceptable excipient can be selected from dextrose, mannitol, lactose monohydrate, lecithin, albumin, sodium glutamate, cysteine hydrochloride, croscarmellose sodium, sodium starch glycolate, hydroxypropyl cellulose, poloxamer, sodium lauryl sulfate, or colloidal silicon dioxide, or any combination thereof. Poloxamers comprise, for example, poloxamer 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403, 407, poloxamer 105 benzoate, or poloxamer 182 dibenzoate 407 or any combination thereof. In one embodiment, the at least one pharmaceutically acceptable excipient can comprise microcrystalline cellulose. In one embodiment, the at least one pharmaceutically acceptable excipient can be an aluminometasilicate, such as sodium aluminometasilicate, magnesium aluminometasilicate, calcium aluminometasilicate, potassium aluminometasilicate, or lithium aluminometasilicate or any combination thereof.
[0276] The amount of the pharmaceutically acceptable excipient may vary from or any number in between 1% to 75% by weight of the total pharmaceutical composition. In some embodiments, the amount of excipient ranges from or any number in between 1-5%, 2- 7%, 5-10%, 7-12%, 10-15%, 12-17%, 15%-20%, 17%-22%, 20%-25%, 22%-27%, 25%- 30%, 27%-32%, 30%-35%, 32%-37%, 35%-40%, 37%-42%, 40%-45%, 40-50%, 45-55%, 50-60%), 55-65%), 60-70%), or 65-75%) by weight of the total pharmaceutical composition or within a range defined by any two of the aforementioned amounts. In some embodiments, the amount of excipient is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 75% of the weight of the total pharmaceutical composition or within a range defined by any two of the aforementioned amounts. In some embodiments, the amount of excipient is less than 5% of the weight of the total pharmaceutical composition but not zero.
[0277] The amounts of excipient can be determined by the dosage of a compound of Formula (I), alone or in combination with an androgen deprivation therapies, anti-estrogen therapies, biologic treatments, virus-based therapies, surgeries, chemotherapies, antineoplastic therapies, radiation therapies, statin treatments, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combination thereof, optionally, wherein the chemotherapy or antineoplastic therapy is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy, and the dosage form size of the total pharmaceutical composition. In some embodiments disclosed herein, the dosage form size of the total pharmaceutical composition is 175 mg. In some embodiments disclosed herein the dosage form size of the total pharmaceutical composition is 350 mg. In some embodiments disclosed herein the dosage form size of the total pharmaceutical composition is 700 mg. One skilled in the art will realize that a range of dosage form sizes of the total pharmaceutical composition can be made and are encompassed by this disclosure. The preferred dosage form size range of the total pharmaceutical composition is from 50 mg to 1500 mg, more typically from 100 mg to 1000 mg, more typically from 175 mg to 700 mg, with the preferred typical dosage form size of the total pharmaceutical composition being 175 mg, 350 mg, or 700 mg or within a range defined by any two of the aforementioned amounts.
[0278] In some embodiments, the at least one pharmaceutically acceptable excipient can be selected from binders, disintegrants, surfactants, or stabilizers. Any one or more of the excipients (including binders, disintegrants, surfactants, or stabilizers) can be appropriate in the pharmaceutical composition containing a compound of Formula (I), alone or in combination with an additional therapy, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies, antineoplastic therapies radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapy or antineoplastic therapy is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy and at least one pharmaceutically acceptable carrier in accordance with the disclosure herein, provided that the compound of Formula (I) or the one or more additional therapies is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with oral administration to a subject.
1. Binders
[0279] In some embodiments, the at least one pharmaceutically acceptable excipient can comprise at least one or more binders. The at least one or more binders can be used, for example, to impart cohesive qualities to a pharmaceutical formulation comprising the compound of Formula (I), alone or in combination with one or more an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies, antineoplastic therapies, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein chemotherapy or antineoplastic therapy is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy and thus permit the resulting dosage form to remain intact during formulation of capsules, tablets, film coated tablets, caplets, gel caps, pill pellets, or beads, suitable for oral administration to a subject. In some embodiments, the one or more binders are selected from microcrystalline cellulose, gelatin, sugars (including, for example, sucrose, glucose, dextrose and maltodextrin), polyethylene glycol, waxes, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, povidone, cellulosic polymers (including, for example, hydroxypropyl cellulose (UPC), hydroxypropyl methylcellulose (UPMC), methyl cellulose, hydroxyethyl cellulose), or hydroxypropyl cellulose (HPC), or any combinations thereof. 2. Disintegrants
[0280] In some embodiments, the at least one pharmaceutically acceptable excipient can comprise one or more disintegrants. The at least one or more disintegrants can be used, for example, to facilitate disintegration of a pharmaceutical composition after oral administration. In some embodiments, the at least one or more disintegrants are selected from starches, clays, celluloses, algins, gums, or crosslinked polymers or any combinations thereof. In some embodiments, the one or more disintegrants are selected from crosslinked polyvinylpyrrolidone (PVP-XL), sodium starch glycolate, alginic acid, methacrylic acid DYB, microcrystalline cellulose, crospovidone, polacriline potassium, sodium starch glycolate, starch, pregelatinized starch, or croscarmellose sodium or any combinations thereof.
3. Surfactants
[0281] In some embodiments, the at least one pharmaceutically acceptable excipient can comprise one or more surfactants. The at least one or more surfactants can be used, for example, as a wetting agent. The at least one or more surfactants can be used, for example, to improve the permeation and/or bioavailability of the compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies, antineoplastic therapy, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combinations thereof, optionally, wherein the chemotherapy or antineoplastic therapy is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy. In some embodiments, the at least one or more surfactants are selected from anionic surfactants, non-ionic surfactants, or zwitterionic surfactants or any mixture thereof. In some embodiments, the one or more surfactants are selected from poly(oxyethylene) sorbitan fatty acid ester, poly(oxyethylene) stearate, poly(oxyethylene) alkyl ether, polyglycolated glyceride, poly(oxyethylene) castor oil, sorbitan fatty acid ester, poloxamer, fatty acid salt, bile salt, alkyl sulfate, lecithin, mixed micelle of bile salt and lecithin, glucose ester vitamin E TPGS (D-a-tocopheryl polyethylene glycol 1000 succinate), or sodium lauryl sulfate or any combinations thereof. 4. Stabilizers
[0282] In some embodiments, the at least one pharmaceutically acceptable excipient can comprise one or more stabilizers. In some embodiments, the at least one or more stabilizers are selected from alkanizing agents, chelating agents, photoprotectants, or antioxidants or any combinations thereof.
[0283] In some embodiments, the alkanizing agent is selected from alkali metal salt additives or an alkaline earth metal salt additive or any combinations thereof. Alkali metal salt additives suitable for use in some embodiments can comprise, for example, sodium carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate or other suitable alkali metal salts or any combinations thereof. Alkaline earth metal salt additives can comprise, for example, calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, or aluminum magnesium hydroxide or any combinations thereof.
[0284] In some embodiments, the chelating agent comprises disodium EDTA, edetic acid, or citric acid, or any combination thereof.
[0285] In some embodiments, a photoprotectant can be used, for example, to protect the pharmaceutical composition from the chemical or physical effects of light. In some embodiments, the photoprotectant is selected from titanium oxide, ferric oxide, or zinc oxide or any combination thereof.
[0286] In some embodiments, the antioxidant is selected from butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulfite, propyl gallate, tocopherol, citric acid, malic acid, or ascorbic acid, or any mixtures thereof. VI. Dosage forms of pharmaceutical compositions of a Compound of Formula (I)
[0287] In some embodiments, a compound of Formula (I) may be formulated as a pharmaceutical composition, alone or in combination with an additional therapy as disclosed herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy suitable for oral administration to a subject. In some embodiments, the pharmaceutical composition is formulated for oral ingestion by a subject as a tablet, pill, capsule, granule, gummy, dragee, liquid, gel, syrup, slurry, spray, or suspension. In some embodiments, the composition is in the form of a tablet, a film coated tablet, a gel cap, a caplet, a pellet, or a bead. In some embodiments, the pharmaceutical composition is in the form of a capsule having a dissolvable enclosure for carrying the compound of Formula (I), alone or in combination with an additional therapy described herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormone deprivation therapy, rmonal therapy, is not a hormone replacement therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy and one or more pharmaceutically acceptable carriers and/or excipients. In one embodiment, a capsule is made of gelatin. In some embodiments, the pharmaceutical composition is in the form of a soft gel capsule.
[0288] Pharmaceutical compositions for oral administration may be obtained by combining a compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy, with one or more pharmaceutically acceptable carriers and/or excipients, optionally grinding the resulting mixture, and processing the mixture, to obtain tablets, pills, capsules, granules, dragees, a liquid, a gel, a syrup, a slurry, a spray, or a suspension. The pharmaceutical compositions comprising a compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti- estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy may be manufactured by mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.
[0289] In some embodiments, the pharmaceutical composition may comprise a coating, for example, a film coating. Where film coatings are involved, coating preparations can comprise, for example, a film-forming polymer, or a plasticizer. Non-limiting examples of film-forming polymers suitable for use in the embodiments described herein comprise hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl pyrrolidine, or starches or any combinations thereof. Non-limiting examples of plasticizers suitable for use in the embodiments described herein comprise polyethylene glycol, tributyl citrate, dibutyl sebecate, or acetylated monoglyceride or any combinations thereof. Dyestuffs or pigments may be added to the pharmaceutical composition or to coatings for the pharmaceutical composition for identification or to characterize different combinations of active compound doses. For this purpose, concentrated sugar solutions may be used, which may optionally comprise gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures or any combinations thereof. Dyestuffs or pigments may be added for identification or to characterize different dosage amounts of a compound of Formula (I), or the one or more additional therapies included in the pharmaceutical composition, and including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy. Non-limiting examples of dyestuffs and pigments suitable for use in the embodiments described herein comprise iron oxides of various colors, lake dyes of many colors, or titanium dioxide or any combinations thereof.
[0290] In some embodiments, the compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy may be formulated as a pharmaceutical composition suitable for administration to a subject rectally, transmucosally, topically, via intestinal administration, parenteral delivery (including intramuscular, subcutaneous, intravenous, and/or intramedullary injections), intrathecally, via direct intraventricular, intraperitoneal, intranasal, or intraocular injection.
[0291] In some embodiments, the pharmaceutical composition is formulated for intranasal administration. In some embodiments, the composition is formulated as a drop, a spray, or an inhalant for administration to the nasal cavity. In some embodiments, a compound of Formula (I) is formulated for intranasal administration alone or in combination with an additional therapy described herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies, such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy and one or more appropriate pharmaceutically acceptable carriers and/or excipients for intranasal administration.
[0292] In some embodiments, the pharmaceutical composition is formulated for parenteral administration. In some embodiments, the composition is formulated as a solution for intraperitoneal, infusion, intramuscular, subcutaneous, intradermal, or intravenous injection. In some embodiments, a compound of Formula (I) is formulated for parenteral administration alone or in combination with an additional therapy described herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies, such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy and one or more appropriate pharmaceutically acceptable carriers and/or excipients for parenteral administration.
[0293] The pharmaceutical composition may be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing a compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy. The pack may for example include metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. The pharmaceutical composition comprising a compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy, may be placed in an appropriate container, and labeled for treatment or inhibition of an indicated condition, such as for treatment or inhibition of a cancer such as bladder cancer or prostate cancer.
[0294] In some embodiments, the pharmaceutical compositions comprising the compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy can be stable for at least, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 24 months, 36 months, or 48 months or within a range defined by any two of the aforementioned times.
VII. Therapeutic Indications
[0295] Some embodiments disclosed herein relate to pharmaceutical compositions comprising the compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus- based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy and methods of using such compositions to inhibit, delay, treat, or prevent bladder or prostate cancer cell growth or bladder or prostate cancer in a subject in need thereof.
A. Pharmaceutical compositions of Compound of Formula (I) as Anticancer Agents
[0296] Pharmaceutical compositions comprising a compound of Formula (I) have significant anti-cancer properties for oral administration to subjects in need of anti-cancer therapy. Without wishing to be bound by theory, it is contemplated that the primary mechanism of cytotoxic action of pharmaceutical compositions comprising a compound of Formula (I) is due to redox-cycling and electrophilic arylation. A compound of Formula (I) may be reduced by electron transfer from flavoprotein to a semiquinone radical, which can, in turn, reduce oxygen to superoxide. The resulting superoxide may consequently be converted into hydrogen peroxide, hydroxyl radicals, and/or peroxynitrite, all of which are highly reactive oxygen species (ROS) with potent cytotoxic and tumoricidial effects.
[0297] While still not wishing to be bound by theory, an additional antitumor mechanism of pharmaceutical compositions including a compound of Formula (I) may involve direct arylation of intracellular thiols leading to depletion of glutathione (GSH). Depletion of GSH may ultimately result in alkylation of cellular macromolecules and in their inactivation. Such activities may contribute to the tumoricidial effects of pharmaceutical compositions including a compound of Formula (I).
[0298] Moreover, while still not wishing to be bound by theory, an additional antitumor mechanism for pharmaceutical compositions including a compound of Formula (I) may involve inhibition of microtubule polymerization and binding to tubulin. Because one of the defining characteristics of cancer cells is a significantly increased rate of cell cycle entry and/or mitosis, cancer cells are more vulnerable to agents that affect microtubule polymerization than normal cells. The compound of Formula (I) may recognize the colchicine binding site of tubulin and inhibit in vitro tubulin polymerization. [0299] Pharmaceutical compositions comprising a compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy exhibit significant and unexpectedly improved (for example, synergy may be obtained) effects for inhibiting, delaying, and preventing the growth of cancer such as bladder cancer or prostate cancer when the pharmaceutical compositions including a compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy are provided to a subject orally. In some embodiments, the administration of a pharmaceutical composition including a compound of Formula (I), alone or in combination with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic treatments, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent, such as a platinum-based antineoplastic agents, radiation therapies, statin treatments, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy, to a subject in need effectively inhibit the growth of cancer cells, such as bladder cancer cells or prostate cancer cells.
[0300] In some embodiments, when the composition comprising a compound of Formula (I) is provided in combination with the additional therapies described herein, an unexpected and surprising reduction, delay, or inhibition in cancer cell growth, such as bladder cancer cell growth or prostate cancer cell growth, is realized. Accordingly, it is preferred that pharmaceutical compositions comprising a compound of Formula (I) are provided in combination or in co-administration with one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
B. Combination Therapies
[0301] In some alternatives, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein can be used in combination with one or more therapies, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy. Some alternatives disclosed herein relate to a method of ameliorating, inhibiting or treating cancer such as bladder cancer or prostate cancer that can comprise administering or providing to a subject suffering from cancer such as bladder cancer or prostate cancer a pharmaceutical composition comprising a compound of Formula (I) in combination with one or more additional agents (referred to as "combination therapy").
[0302] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) is administered to a patient instead of anti-AR drugs to prevent recurrence in patients previously experiencing a therapy for cancer, such as bladder cancer (including high risk non muscle-invasive bladder cancer) or prostate cancer. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) is administered to patients who have become resistant to cancer therapies, such as resistant to enzalutamide or to other AR antagonists and still display AR activity. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) may be used in combination with an additional agent as described herein, including one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
[0303] Provided herein are methods of preventing or inhibiting recurrence of cancer such as bladder cancer or prostate cancer, including selecting a patient who has previously received a therapy for cancer, such as bladder cancer (including high risk bladder cancer) or prostate cancer, and administering a composition comprising a compound of Formula (I), alone or in combination with of one or more of an androgen deprivation therapies, anti-estrogen therapies, biologic therapies, virus-based therapies, surgeries, chemotherapies such as taxane-based chemotherapy agents, an antineoplastic agent such as a platinum-based antineoplastic agents, radiation therapies, statin therapies, repurposed drug therapies, small molecule inhibitor therapies, therapeutic antibody therapies, or immunotherapies or any combinations thereof, optionally, wherein the chemotherapeutic agent, chemotherapy, or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
[0304] Thus, in some embodiments, the methods include selecting a subject who is suffering from cancer such as bladder cancer or prostate cancer and administering a composition comprising a compound of Formula (I). In some embodiments, the subject is selected who has previously received a therapy for cancer, such as bladder cancer (including high risk bladder cancer) or prostate cancer. In some embodiments, the subject is selected who is in need of cancer treatment. In some embodiments, the subject is selected who has developed a recurrence of cancer. In some embodiments, the subject is selected who has developed a resistance to cancer treatments, such as resistance to enzalutamide or other androgen receptor antagonists and yet still displays androgen receptor activity. In some embodiments, a subject is selected who has any combination of the aforementioned selection criteria.
[0305] In some embodiments, the methods comprise selecting a subject as described herein who is suffering from cancer such as bladder cancer or prostate cancer, and administering a composition including a compound of Formula (I) in combination with an androgen deprivation therapy (ADT). In some embodiments, the ADT comprises a surgical method of ADT, such as surgical orchiectomy. In some embodiments, the ADT comprises a pharmaceutical-based ADT comprising administration of an agent, comprising orteronel, cyproterone acetate, flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, galeterone, abiraterone, finasteride, ethylstilbestrol (DES), megestrol acetate, fosfestrol, estramustine phosphate, leuprolide, triptorelin, goserelin, histrelin, buserelin, abarelix, degarelix, or derivatives, salts, or analogues thereof, or any combinations thereof.
[0306] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with surgical orchiectomy. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with orteronel. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with cyproterone acetate. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with flutamide. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with nilutamide. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with bicalutamide. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with enzalutamide. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with apalutamide. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with galeterone. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with abiraterone. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with finasteride. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ethylstilbestrol (DES). In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with megestrol acetate. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with fosfestrol. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with estramustine phosphate. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with leuprolide. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with triptorelin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with goserelin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with histrelin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with buserelin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with abarelix. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with degarelix.
[0307] In some embodiments, the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with an anti-estrogen therapy (anti-ER therapy). In some embodiments, the anti-ER therapy comprises a surgical method of anti-ER therapy, e.g., surgical ovariectomy. In some embodiments, the anti-ER therapy comprises a pharmaceutical-based anti-ER therapy, comprising administration of tamoxifen, clomifene, ormeloxifene, toremifene, lasofoxifene, ospemifene, raloxifene, fulvestrant, brilanestrant, elacestrant, anastrozole, letrozole, testolactone, exemestane, or derivatives, salts, or analogues thereof, or combinations thereof.
[0308] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ovariectomy. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with tamoxifen. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with clomifene. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ormeloxifene. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with toremifene. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with lasofoxifene. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ospemifene. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with raloxifene. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with fulvestrant. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with brilanestrant. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with elacestrant. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with anastrozole. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with letrozole. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with testolactone. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with exemestane.
[0309] In some embodiments, the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a biologic. In some embodiments, a biologic comprises Bacillus Calmette-Guerin (BCG) vaccine, sargramostim, filgrastim, pegfilgrastim, recombinant interleukin-12, or interferon alpha, or a combination thereof.
[0310] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with Bacillus Calmette-Guerin (BCG) vaccine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with sargramostim. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with filgrastim. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pegfilgrastim. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with recombinant interleukin-12. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with interferon alpha.
[0311] In some embodiments, the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a virus-based therapy. In some embodiments, a virus-based therapy comprises use of a reovirus, bunyavirus, flavivirus, rubivirus, filovirus, arenavirus, arterivirus, calicivirus, a retrovirus, an adenoviral vector, (including the oncolytic adenovirus vector CG0070 (Cold Genesys)), or a Coxsackievirus A21 (CVA21; CAVATAK, Viralytics), or a combination thereof.
[0312] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with reovirus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with bunyavirus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with flavivirus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with rubivirus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with filovirus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with arenavirus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with arterivirus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with calicivirus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with a retrovirus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with an adenoviral vector (comprising the oncolytic adenovirus vector CG0070 (Cold Genesys)). In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with a Coxsackievirus A21 (CVA21; CAVATAK, Viralytics).
[0313] In some embodiments, the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a chemotherapy, optionally, wherein the chemotherapeutic agent or chemotherapy is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy. In some embodiments, a chemotherapy comprises gemcitabine, cyclophosphamide, methotrexate, 5- fluorouracil, doxorubicin, mustine, vincristine, procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, etoposide, epirubicin, capecitabine, methotrexate, folinic acid, lenalidomide, pemetrexed, azacitidine and analog decitabine, mitomycin C, apaziquone, eribulin, valrubicin, vinflunine, pirarubicine, pralatrexate, temsirolimus, sirolimus, ifosfamide, irinotecan, rubitecan, or AZD4877, or combinations thereof.
[0314] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with gemcitabine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with cyclophosphamide. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with methotrexate. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with 5-fluorouracil. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with doxorubicin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with mustine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with vincristine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with procarbazine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with prednisolone. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with bleomycin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with vinblastine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with dacarbazine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with etoposide. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with epirubicin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with capecitabine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with methotrexate. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with folinic acid. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with lenalidomide. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pemetrexed. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with azacitidine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with decitabine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with mitomycin C. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with apaziquone. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with eribulin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with valrubicin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with vinflunine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pirarubicine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pralatrexate. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with temsirolimus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with sirolimus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ifosfamide. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with irinotecan. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with rubitecan. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with AZD4877.
[0315] In some embodiments, the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a taxane-based chemotherapy agent. In some embodiments, a taxane-based chemotherapy agent comprises docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or combinations, analogues, derivatives, emulsions, pro-drugs, and/or lipid conjugates, or polymers thereof or any combination thereof.
[0316] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with docetaxel. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with paclitaxel. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with cabazitaxel. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with 5- larotaxel. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ortataxel. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with milataxel. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with tesetaxel. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with abraxane.
[0317] In some embodiments, the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a platinum-based antineoplastic agent. In some embodiments, a platinum-based antineoplastic agent comprises cisplatin, carboplatin, dicycloplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, or satraplatin, or analogues or derivatives thereof or any combinations thereof. [0318] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with cisplatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with carboplatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with dicycloplatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with 5- oxaliplatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with nedaplatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with triplatin tetranitrate. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ormaplatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with phenanthriplatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with picoplatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pyriplatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with satraplatin.
[0319] In some embodiments, the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a radiation therapy. In some embodiments, radiation therapy comprises internal or external radiotherapy. In some embodiments, internal radiotherapy comprises positioning the source of radioactivity inside the body close to the tumor through brachytherapy or radioisotope therapy. In some embodiments, external radiotherapy comprises targeting doses of high- energy beams of radiation to the tumor.
[0320] In some embodiments, the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a statin. In some embodiments, the statin comprises atorvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, or combinations thereof, or a combination of a statin and another agent, such as ezetimibe/simvastatin.
[0321] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with atorvastatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with fluvastatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with lovastatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with mevastatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pitavastatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pravastatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with rosuvastatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with simvastatin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ezetimibe/simvastatin.
[0322] In some embodiments, the method comprises selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a repurposed drug therapy. In some embodiments, a repurposed drug therapy comprises eflornithine, indinavir, metformin, or ritonavir, or any combination thereof.
[0323] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with eflornithine. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with indinavir. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with metformin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ritonavir.
[0324] In some embodiments, the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a small molecule inhibitor therapy. In some embodiments, a small molecule inhibitor therapy comprises administration of belinostat, bortezomib, copanlisib, crizotinib, imatinib, dasatinib, dovitinib, rapamycin, everolimus, sirolimus, tipifarnib, pazopanib, alisertib, sapanisertib, lapatinib, lonafarnib, merestinib, olaparib, palbociclib, bosutinib, sorafenib, erlotinib, sunitinib, cabozantinib, gefitinib, ixazomib, vistusertib, vorinostat, entinostat vandetanib, BAY1163877, MLN8054, PLX3397, or BGJ398, or any combinations thereof.
[0325] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with belinostat. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with bortezomib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with copanlisib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with crizotinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with imatinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with dasatinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with dovitinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with rapamycin. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with everolimus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with sirolimus. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with tipifarnib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pazopanib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with alisertib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with sapanisertib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with lapatinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with lonafarnib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with merestinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with olaparib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with palbociclib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with bosutinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with sorafenib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with erlotinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with sunitinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with cabozantinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with gefitinib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ixazomib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with vistusertib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with vorinostat. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with entinostat. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with vandetanib. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with BAY1 163877. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with MLN8054. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with PLX3397. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with BGJ398.
[0326] In some embodiments, the methods comprise selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a therapeutic antibody therapy. In some embodiments, a therapeutic antibody therapy comprises cetuximab, ritixumab, bevacizumab, ranibizumab, trastuzumab, or panitumumab, fragments thereof, or any combinations thereof, which may be present on one or more CAR T cells.
[0327] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with cetuximab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ritixumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with bevacizumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ranibizumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with trastuzumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with panitumumab.
[0328] In some embodiments, the method includes selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with an immunotherapy. In some embodiments, an immunotherapy comprises nivolumab, durvalumab, pembrolizumab, atezolizumab, ipilimumab, tremelimumab, CA-170, NEO-PV- 01, a tumor cell-derived vaccine therapy, or any combination thereof.
[0329] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with nivolumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with durvalumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with pembrolizumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with atezolizumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with ipilimumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with tremelimumab. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with CA-170. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with NEO-PV-01. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein may be used in combination with a tumor cell-derived vaccine therapy.
[0330] In some embodiments, the method comprises selecting a subject as described herein who is suffering from cancer, such as bladder cancer or prostate cancer, and administering a composition comprising a compound of Formula (I) in combination with a combination of one or more of orteronel, cyproterone acetate, flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, galeterone, abiraterone, finasteride, ethylstilbestrol (DES), megestrol acetate, fosfestrol, estramustine phosphate, leuprolide, triptorelin, goserelin, histrelin, buserelin, abarelix, degarelix, tamoxifen, clomifene, ormeloxifene, toremifene, lasofoxifene, ospemifene, raloxifene, fulvestrant, brilanestrant, elacestrant, anastrozole, letrozole, testolactone, exemestane, Bacillus Calmette-Guerin (BCG) vaccine, sargramostim, filgrastim, pegfilgrastim, recombinant interleukin-12, interferon alpha, reovirus, bunyavirus, flavivirus, rubivirus, filovirus, arenavirus, arterivirus, calicivirus, a retrovirus, an adenoviral vector, (including the oncolytic adenovirus vector CG0070 (Cold Genesys)), a Coxsackievirus A21 (CVA21; CAVATAK, Viralytics), gemcitabine, cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, mustine, vincristine, procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, etoposide, epirubicin, capecitabine, methotrexate, folinic acid, lenalidomide, pemetrexed, azacitidine and analog decitabine, mitomycin C, apaziquone, eribulin, valrubicin, vinflunine, pirarubicine, pralatrexate, temsirolimus, sirolimus, ifosfamide, irinotecan, rubitecan, AZD4877, cisplatin, carboplatin, dicycloplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, satraplatin, docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, abraxane, radiation therapy, atorvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe/simvastatin, eflornithine, indinavir, metformin, ritonavir, belinostat, bortezomib, copanlisib, crizotinib, imatinib, dasatinib, dovitinib, rapamycin, everolimus, sirolimus, tipifarnib, pazopanib, alisertib, sapanisertib, lapatinib, lonafarnib, merestinib, olaparib, palbociclib, bosutinib, sorafenib, erlotinib, sunitinib, cabozantinib, gefitinib, ixazomib, vistusertib, vonnostat, entinostat vandetanib, BAYl 163877, MLN8054, PLX3397, BGJ398, cetuximab, ritixumab, bevacizumab, ranibizumab, trastuzumab, panitumumab nivolumab, durvalumab, pembrolizumab, atezolizumab, ipilimumab, tremelimumab, CA-170, EO-PV- 01, a tumor cell-derived vaccine therapy, or derivatives, analogues, any combinations, emulsions, pro-drugs, lipid conjugates, pharmaceutically acceptable salts thereof, or polymers thereof.
[0331] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) as described herein is used in combination with one or more additional therapy as described herein for the use in treating, inhibiting, delaying, or ameliorating progression of bladder cancer, comprising high risk bladder cancer, stage 0a, stage Ois, I, stage II, stage III, or stage IV bladder cancer growth of bladder cancer cells, or for inhibiting or preventing the onset of bladder cancer, or for decreasing the size of a bladder tumor, or for inhibiting the onset of metastasis associated with bladder cancer. In some alternatives, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein is used in combination with one or more additional therapy as described herein for the use in increasing the survival rate of a patient suffering from bladder cancer. [0332] In some alternatives, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein is used in combination with an additional therapy described herein for the use in increasing the survival rate of a patient suffering from bladder cancer. In some alternatives, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein is used in combination with an additional therapy described herein for the use in reducing the size of a tumor or further expansion of cancer cells in a patient suffering from bladder cancer, such as stage 0a, stage Ois, stage I, stage II, stage III, or stage IV bladder cancer, or high risk non muscle-invasive bladder cancer. Some alternatives involve methods for inducing remission of bladder cancer, such as stage 0a, stage Ois, stage I, stage II, stage III, or stage IV bladder cancer, or high risk non muscle- invasive bladder cancer, whereby a pharmaceutical composition comprising a compound of Formula (I) disclosed herein is provided before, during, and/or after providing an additional therapy described herein to a subject suffering from bladder cancer. In some alternatives, the methods disclosed herein can result in complete remission of bladder cancer, such as stage 0a, stage Ois, stage I, stage II, stage III, or stage IV bladder cancer, or high risk non-muscle invasive bladder cancer. In some alternatives, the methods can result in partial remission of bladder cancer, such as stage 0a, stage Ois, stage I, stage II, stage III, or stage IV bladder cancer, or high risk non-muscle invasive bladder cancer.
[0333] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) as described herein is used in combination with one or more additional therapy as described herein for the use in treating, inhibiting, delaying, or ameliorating progression of prostate cancer, such as stage I, stage II, stage III or stage IV prostate cancer. In some alternatives, the prostate cancer can be castration resistant prostate cancer (CRPC), a prostate cancer that has extended beyond the outer condensed fibromuscular band, also known as the capsule, or metastasis stemming from prostate cancer. In some alternatives, the prostate cancer is androgen dependent. Therefore, in some alternatives, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used in combination with one or more additional therapy described herein for the use in treating, inhibiting, delaying, or ameliorating progression of prostate cancer, such as stage I, stage II, stage III or stage IV prostate cancer growth of prostate cancer cells, or for inhibiting or preventing the onset of androgen-dependent prostate cancer, or for decreasing the size of a prostate tumor, or for inhibiting the onset of metastasis associated with prostate cancer. In some alternatives, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used in combination with one or more additional therapy described herein for the use in increasing the survival rate of a patient suffering from prostate cancer.
[0334] Normal serum testosterone ranges between 1000-300 ng/dL. In some alternatives, a subject is provided a combination therapy, as described herein, whereby a reduction in the treated subject's serum testosterone level to at least < 80, < 70, < 60, < 50, < 40, < 30, < 20, or < 10 ng/dL is obtained. In some alternatives, a subject is provided a combination therapy that reduces the subject's serum testosterone level to at least < 50 ng/dL. In some alternatives, a subject is treated with a combination therapy that results in a reduction in the subject's serum testosterone level to at least < 20 ng/dL. In some alternatives, a subject is treated with a combination therapy, as described herein, that reduces the subject's serum testosterone level to at least or any number in between the range of 120- 70, 100-60, 80-40, 70-30, 50-20, 40-10, 30-10, or 20-10 ng/dL. In some alternatives, a subject is treated with a combination therapy that produces a reduction in the subject's serum testosterone level to < 95%, < 90%, < 80%, < 70%, < 60%, or < 50% that of a healthy male. In some alternatives, a subject is treated with a combination therapy that results in a reduction in the subject's serum testosterone level to the range of at least or any number in between the range of 5-20%, 10-30%, 20-40%, 30-50%, 40-60%, or 50-70% that of a healthy male. In some alternatives, a subject is treated with a combination therapy that results in a reduction in the subject's serum testosterone level to the range of at least or any number in between the range of 1-2%, 2-4%, 1-5%, 4-6%, 4-8%, or 5-10% that of a healthy male.
[0335] Intermittent hormonal therapy (IHT) is an alternative to continuous hormonal therapy, which may delay progression of hormone-refractory disease (i.e., CRPC). For example, intermittent therapy can be used for a period of 6 months on, followed by a period of 6 months off. In some alternatives, one or more hormonal therapy agents is provided for one month on, followed by one month off. In some alternatives, one or more therapy agents are provided for three months on, followed by three months off. Accordingly, one or more of the compounds of Formula (I) can be provided before, during and/or after administering one or more hormonal therapy agents, as described above, so as to reduce or inhibit or delay the onset of CRPC. Standard of care for metastatic CRPC may include taxane-based chemotherapies, such as docetaxel therapy.
[0336] In some embodiments, administration of a pharmaceutical composition comprising a compound of Formula (I), alone or in combination with one or more additional therapy as described herein to a subject according to any one of the methods disclosed herein results in survival of the subject for at least 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 24 months, 36 months, or 48 months or within a range defined by any two of the aforementioned times. In some embodiments, administration of a pharmaceutical composition comprising a compound of Formula (I) to a subject according to any one of the methods disclosed herein results in survival of the subject for more than 48 months. In some embodiments, administration of a pharmaceutical composition comprising a compound of Formula (I) to a subject according to any one of the methods disclosed herein results in survival of the subject for more than 60 months.
[0337] The order of administration of a pharmaceutical composition comprising a compound of Formula (I) disclosed herein with one or more additional therapy as described herein can vary. In some alternatives, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein can be administered prior to all additional therapy described herein. In other alternatives, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein can be administered prior to at least one additional therapy described herein. In still other alternatives, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein can be administered concomitantly with one or more additional therapy described herein. In yet still other alternatives, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein can be administered subsequent to the administration of at least one additional therapy described herein. In some alternatives, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein can be administered subsequent to the administration of all additional therapy described herein.
[0338] In some alternatives, a subject suffering from cancer such as bladder cancer or prostate cancer, is provided surgical orchiectomy or surgical ovariectomy. In some alternatives, a pharmaceutical composition including a compound of Formula (I) disclosed herein can be administered after surgical orchiectomy or surgical ovariectomy. In some alternatives, a pharmaceutical composition including a compound of Formula (I) disclosed herein can be administered before and after surgical orchiectomy or surgical ovariectomy. VIII. Dosage amounts of a Compound of Formula (I)
[0339] In some embodiments, the pharmaceutical composition comprising a compound of Formula (I) disclosed herein may contain between 0.01 mg and 3000 mg of a compound of Formula (I), preferably between 1 mg and 700 mg, e.g. 5 to 200 mg. In non- human animal studies, applications of potential products are commenced at higher dosage levels, with dosage being decreased until the desired effect is no longer achieved or adverse side effects disappear.
[0340] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) contains an amount of a compound of Formula (I) of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, or 1500 mg or an amount that is within a range defined by any two of the aforementioned amounts.
[0341] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) contains an amount of a compound of Formula (I) of 0.25 mg per kg body weight of the subject, 0.30 mg per kg body weight of the subject, 0.35 mg per kg body weight of the subject, 0.40 mg per kg body weight of the subject, 0.45 mg per kg body weight of the subject, 0.50 mg per kg body weight of the subject, 0.55 mg per kg body weight of the subject, 0.60 mg per kg body weight of the subject, 0.65 mg per kg body weight of the subject, 0.70 mg per kg body weight of the subject, 0.75 mg per kg body weight of the subject, 0.80 mg per kg body weight of the subject, 0.85 mg per kg body weight of the subject, 0.90 mg per kg body weight of the subject, 0.95 mg per kg body weight of the subject, 1.0 mg per kg body weight of the subject, 1.1 mg per kg body weight of the subject, 1.2 mg per kg body weight of the subject, 1.3 mg per kg body weight of the subject, 1.4 mg per kg body weight of the subject, 1.5 mg per kg body weight of the subject, 1.6 mg per kg body weight of the subject, 1.7 mg per kg body weight of the subject, 1.8 mg per kg body weight of the subject, 1.9 mg per kg body weight of the subject, 2 mg per kg body weight of the subject, 3 mg per kg body weight of the subject, 4 mg per kg body weight of the subject, 5 mg per kg body weight of the subject, 6 mg per kg body weight of the subject, 7 mg per kg body weight of the subject, 8 mg per kg body weight of the subject, 9 mg per kg body weight of the subject, 10 mg per kg body weight of the subject, 15 mg per kg body weight of the subject, 20 mg per kg body weight of the subject, 25 mg per kg body weight of the subject, 30 mg per kg body weight of the subject, 35 mg per kg body weight of the subject, 40 mg per kg body weight of the subject, 45 mg per kg body weight of the subject, 50 mg per kg body weight of the subject, 60 mg per kg body weight of the subject, 70 mg per kg body weight of the subject, 80 mg per kg body weight of the subject, 90 mg per kg body weight of the subject, or 100 mg per kg body weight of the subject or an amount that is within a range defined by any two of the aforementioned amounts.
[0342] In some embodiments, the amount of comprising a compound of Formula (I) may vary from or any number in between 10% to 75% by weight of the total pharmaceutical composition. In some embodiments, the amount of comprising a compound of Formula (I) ranges from or any number in between 10-15%, 12-17%, 15-20%, 17-22%, 25%-30%, 27%-32%, 30%-35%, 32%-37%, 35%-40%, 37%-42%, 40%-45%, 42%-47%, 45%-50%, 47%-52%, 50%-55%, 52%-57%, 55%-60%, 67%-72%, or 70%-75% by weight of the total pharmaceutical composition or an amount that is within a range defined by any two of the aforementioned amounts. In some embodiments, the amount of comprising a compound of Formula (I) is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%), at least 65%, at least 70%, or at least 75%, of the weight of the total pharmaceutical composition or an amount that is within a range defined by any two of the aforementioned amounts.
[0343] The dosage may be a single dosage or a series of two or more given in the course of one or more days, as is needed by the subject. In some alternatives, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein will be administered for a period of continuous therapy, for example for a week or more, or for months or years. In some alternatives, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein can be administered one time per day. [0344] Multiple doses of a pharmaceutical composition comprising a compound of Formula (I) can be administered to a subject. For example, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein can be administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid), over a period of time ranging from one day to one week, from two weeks to four weeks, from one month to two months, from two months to four months, from four months to six months, from six months to eight months, from eight months to 1 year, from 1 year to 2 years, or from 2 years to 4 years, or more.
[0345] In some alternatives, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein and an additional therapy described herein can be cyclically administered to a patient. Cycling therapy involves the administration of a first active ingredient for a period of time, followed by the administration of a second active ingredient for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more therapies, avoid or reduce the side effects of one or more therapies, and/or improve the efficacy of the therapy. In some alternatives, a pharmaceutical composition comprising a compound of Formula (I) disclosed herein and an additional therapy described herein are administered in a cycle of less than 3 weeks, once every two weeks, once every 10 days, or once every week. The number of cycles can be from 1 to 12 cycles, or from 2 to 10 cycles, or from 2 to 8 cycles.
[0346] The daily dosage regimen for an adult human patient may be the same or different for two active ingredients provided in combination. In some alternatives, the active ingredient is a compound of Formula (I). In some alternatives, the active ingredient is a therapy agent as described herein. In some alternatives, both an active ingredient including a compound of Formula (I) and an active ingredient of an additional therapy agent are administered to a subject. For example, a compound of Formula (I) can be provided at a dose of between 0.01 mg and 3000 mg, while an additional therapy agent can be provided at a dose of between 1 mg and 700 mg. The dosage or each active ingredient can be, independently, a single one or a series of two or more given in the course of one or more days, as is needed by the subject. In some alternatives, the active ingredients will be administered for a period of continuous therapy, for example for a week or more, or for months or years. In some alternatives, a pharmaceutical composition including a compound of Formula (I) disclosed herein can be administered one time per day. In some alternatives, the additional therapy agent can be administered once a week.
[0347] In instances where human dosages for active ingredients have been established for at least some condition, those same dosages may be used, or dosages that are between 0.1% and 500%>, more preferably between 25% and 250%> of the established human dosage. Where no human dosage is established, as will be the case for newly-discovered pharmaceutical compositions, a suitable human dosage can be inferred from ED50 or IDso values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
[0348] As will be understood by those of skill in the art, in certain situations it may be necessary to administer the active ingredients disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases.
[0349] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each active ingredient but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90%> of the time, preferably between 30-90%> and most preferably between 50-90%>. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
[0350] Active ingredients disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular active ingredient, or of a subset of the active ingredients, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The efficacy of a particular active ingredient may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.
[0351] The toxicology of a pharmaceutical composition including a compound of Formula (I) may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. The toxicity of a pharmaceutical composition including a compound of Formula (I) may be established by determining in vivo toxicity in an animal model, such as mice, rats, rabbits, or monkeys.
EXAMPLES
[0352] Additional alternatives are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.
General Procedures and Methods
Cell culture
[0353] Bladder cells: mouse urothelial carcinoma MB49 cells were derived from a syngeneic mouse model of bladder cancer that has been widely used for more than 35 years (Summerhayes et al. 1979). MB49 cells recapitulate a key feature of bladder cancer: tumors formed in animals using MB49 cells grow significantly better in male mice than female mice (White-Gilbertson et al. Bladder, 2016, 3, ell). Other mouse bladder cancer cells may be used as well. Stable expression of H2B-GFP in mouse cancer cells was achieved as described previously (Abedinpour et al. Prostate, 2013, 73, 489-499; Abedinpour et al. Prostate, 2011, 71, 813-823).
[0354] A collection of 8 human bladder cancer cell lines with various genetic mutations representative of human cancer were purchased from ATCC (American Type Culture Collection, Manassas, VA). Half of these cell lines have been shown to be positive for AR while at least one of the cell lines has been shown to lack AR.
[0355] All cell lines were grown in their appropriate culture medium, such as, for example, DMEM containing 2mM L-glutamine, glucose (4.5g/ml), Glutamine, 10% FBS (Fetal Bovine Serum), 100 U/ml penicillin and 100 μg/ml streptomycin. Human bladder cancer cells (urothelial carcinoma) were grown in high-glucose DMEM (Dulbecco's Modified Eagle's Medium) containing 10% FBS (fetal bovine serum), 2 mM L-glutamine, and 100 U/mL penicillin/100 μg/mL streptomycin. Geneticin G418 was added to the growth medium of bladder cancer cells transfected with H2B-GFP to maintain expression of the transfected protein.
[0356] Prostate cells: PTEN-P2/GFP are cells that stably express histone H2B- GFP fusion protein. Kanda et al. {Kanda T, Sullivan KF, Wahl GM. Histone-GFP fiision protein enables sensitive analysis of chromosome dynamics in living mammalian cells. Curr Biol 1998 Mar 26;8(7):377-85). These investigators developed a highly sensitive method for observing chromosome dynamics in living cells. They fused the human Histone H2B gene to the gene encoding the GFP, which was transfected into human HeLa cells to generate a stable line constitutively expressing H2B-GFP. The H2B-GFP fusion protein was incorporated into chromatin without affecting cell cycle progression. cDNA encoding a Histone H2B-GFP fusion protein under the 5'LTR in the LXRN retroviral cassette was generated, and introduced into a number of humans, as well as murine cancer cell lines by retroviral transduction.
[0357] Cells were grown in phenol red-free DMEM medium containing 10% FBS, 2 mM L-glutamine, 100 U/ml penicillin/100 μg/ml streptomycin, insulin-selenium- transferrin (5 μg/ml insulin), and DHT 10"8 M final. Cells were maintained in a humidified incubator at 37°C and 5% CO2. G418 (100 μg/ml) was added to maintain stable expression of H2B-GFP.
Cell Viability
[0358] Cells were contacted with a chemotherapy agent, with a compound of Formula (I), or with combinations of a chemotherapy agent and a compound of Formula (I). In these experiments, cells were plated in 96-weil plates in normal growth medium. One or two days after plating, cells were contacted with increasing concentrations of drug for 24 hours. Because tested chemotherapy agents (other than cisplalin) are soluble in DMSO, cells were contacted with DMSO as control and the concentration of DMSO was maintained constant across the range of concentrations. In experiments were cisplatin was used, phosphate buffer saline was used as diluent and as control. Cell viability was assessed by adding 10 μΕ/well of WST-1 reagent (Takara), which quantifies the mitochondrial activity of live cells. After 2 hours the optical density (OD) was measured at 430nm using a spectrophotometer (plate reader Molecular Devices; Spectra Max 250). The blank was measured from wells that did not contain cells and subtracted from all readings. Means of triplicates were calculated for each data point.
Mouse models
[0359] All procedures involving mice were approved by the Institutional Animal Care and Use Committee of Explora Biolabs (San Diego, CA) and carried out according to NIH recommended procedures and precautions. All mice were purchased from Jackson laboratory (Bar Harbor, ME). Mice were about 6 to 8 weeks old, and weigh about 20-25 g at the start of the experiments. Mice were housed at a maximum of two per cage, under standard room conditions, with ad libidum food and water. Every effort was made to minimize animal suffering.
Surgical techniques
[0360] Mice were anesthetized before surgery and received analgesics after surgery according to IACUC-approved procedures. Surgeries were performed in a sterile laminar flow hood with proper instrument sterilization and approved procedures.
Dorsal skinfold chamber, bladder tissue graft, and tumor cell spheroids
[0361] Dorsal skinfold chambers and surgical instruments were autoclaved before use. Saline used to keep tissue moist during surgical preparation was mixed with gentamicin
Figure imgf000105_0001
[0362] Male Nude mice (25-35 g body weight) were anesthetized (7.3 mg ketamine hydrochloride and 2.3 mg xylazine /100 g body weight, i.p.) and placed on a heating pad. Two symmetrical titanium frames were implanted into a dorsal skinfold, so as to sandwich the extended double layer of skin. A 15 mm full thickness circular layer was excised. The underlying muscle and subcutaneous tissues were covered with a glass coverslip incorporated in one of the frames. After a recovery period of 2-3 days, bladder tissue and cancer cell spheroids were carefully placed in the chamber. Small circular Band Aids were applied on the backside of the chamber after surgery to prevent scratching. Before surgery, Buprenorphine (0.1 mg/kg) was given IP. After surgery, Meloxicam was given in the drinking water for 4 days. Meloxicam (5.0 mg/mL) was added at 35 μΙ_, per 100 mL of water to be medicated. [0363] Liquid overlay plates were generated using 1% molecular biology grade agarose melted in cell culture medium and plated in round bottom 96 well plates at 50ul/well. Tumor cells grown as pre-confluent monolayers were trypsinized and diluted to a final volume of 1,000,000 cells/ml. Viability was determined by Trypan blue. Cells were placed onto the cooled agarose (70 μΐ/well) and allowed to compact into spheroids for 24 hours. The spheroids were picked with a pipette and transferred into serum-free media for implantation in the chambers.
Intravital Microscopy (IVM)
[0364] Intravital Microscopy (IVM) can be used to visualize tumors in animals and analyze various aspects of cancer physiology such as tumor vascularization, cell migration and metastasis. An advantage of IVM includes the real-time analysis of dynamic processes with single-cell resolution. IVM offers the possibility to follow tumor growth in a non-invasive, non-destructive manner. The application of IVM can be limited to animal models that bear visually accessible tumors. Therefore, the dorsal skinfold chamber model described above can be compatible with IVM. Using IVM can permit a number of parameters to be measured in living animals and as a function of time, including tumor growth, angiogenesis, infiltration by immune cells, tumor cell migration, mitosis (cell- division) and apoptosis (programmed cell death), all in the context of the host and in real time. Tumor growth experiments in vivo were performed using IVM in a pseudo-orthotopic chamber model as previously described. In summary, titanium chambers were placed by surgery in nude mice and syngeneic bladder tissue was grafted into the chamber two days later. Tumor spheroids containing 50,000 to 70,000 H2B-GFP-positive mouse bladder cancer cells were placed on the grafted bladder tissue 7 days later, once the tissue was vascularized. Two days later, the mice were castrated or treated with the drug of interest (for example, placebo, androgen deprivation therapy, anti-estrogen therapy, a biologic, a virus-based therapy, surgery, chemotherapy, antineoplastic agent, radiation therapy, statin, repurposed drug therapy, small molecule inhibitor therapy, therapeutic antibody therapy, immunotherapy, or combinations thereof, optionally, wherein the chemotherapy or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti- estrogen therapy) a day before initiation of the treatment with a compound of Formula (I). Orthotopic mouse model of bladder cancer using transurethral cancer cell injection
[0365] Orthotopic tumor inoculation was performed by transducing MB49 mouse bladder tumor cells with a lentiviral construct to stably express the firefly luciferase gene. These cells have been certified free of rodent pathogens. They were cultured in normal growth medium before injection into mice. Experiments looking at the efficacy of ADT on tumor growth were performed using 10 week-old C57/B16 male mice. Other experiments were performed in both female and male mice.
[0366] Mice were anesthetized and placed on a heating pad. A catheter was placed through the urethra with the stylet removed. The bladder was drained of urine, and a platinum wire was inserted through the catheter for cauterization of the bladder wall (Dobek and Godbey (2011); An Orthotopic Model of Murine Bladder Cancer. JoVE. 48). The wire was removed and MB49 cells were instilled through the catheter into the bladder.
[0367] Once the cells attached to the bladder wall and a tumor was growing, mice were contacted with each drug of interest, alone or in combination, according to the drug route of administration and schedule. For example, a compound of Formula (I) can be administered per oral in drinking water or by gavage five days a week.
[0368] Tumor growth was assessed in real-time by animal imaging using a Caliper Life Sciences IVIS Lumina II Imager that takes advantage of luciferase expression by the tumor cells. Imaging was performed twice a week. If metastasis was visible, the number and size of metastatic tumors was recorded. Mice were killed at the end of the experiment according to IACUC-approved procedure and the tumor was resected. A portion of the tumor tissue was fixed in formaldehyde for IHC (immunohistochemistry) staining and another portion of tumor tissue was flash-frozen for gene expression and protein analysis. Survival studies
[0369] A well-established carcinogen-induced bladder cancer model was used. Mice were administered, for example, 0.05% BBN (N-butyl-N-(4-hydroxybutyl) nitrosamine) in their drinking water continuously for eight weeks, which induces the formation of tumors in the bladder. After 8 weeks of BBN exposure, animals resumed drinking water without BBN. Mice were then surgically castrated or started on androgen deprivation therapy, anti-estrogen therapy, a biologic, a virus-based therapy, surgery, chemotherapy, antineoplastic agent, radiation therapy, statin, repurposed drug therapy, small molecule inhibitor therapy, therapeutic antibody therapy, immunotherapy, or combinations thereof, optionally, wherein the chemotherapy or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy. Treatment with a compound of Formula (I) was initiated 2-4 days later. The number of days mice lived following treatment initiation was recorded for each animal. Mice were euthanized by a technician blinded to the study when they lost more than 15% of their weight or showed signs of pain though posture and lack of grooming, whichever came first, in agreement with our IACUC regulations. Once euthanized, the mice were necropsied for tissue harvesting and examination. The tumor was excised, and halt of the tumor tissue was flash-frozen while the other half was immerged in para-formaldehyde for immuno-histology.
Administration of a compound of Formula (I)
[0370] Unless otherwise indicated, a composition including a compound of Formula (I) was administered by oral gavage. The composition was prepared by dissolving a compound of Formula (I) in DMSO then in oil at a concentration of 0.25 mg/mL (weight/volume) with a final DMSO concentration of 0.5% (vol/vol), and administered to mice at a dose of 1 mg/kg.
Statistical analysis
[0371] Means of tumor sizes within treatment groups and standard errors were calculated. The statistical significance of differences within treatment arms (i.e. efficacy of a treatment as a function of time) was calculated using one-way repeated-measures ANOVA with post hoc Bonferroni correction. The statistical significance of differences between treatment arms was calculated using two-way repeated-measures ANOVA with post hoc Bonferroni correction. The difference between survival curves was calculated using the non- parametric log-rank test.
Example 1
In Vitro Effects of Compounds of Formula (I) on Prostate Cancer Cells
[0372] Prostate cancer cells were grown in their appropriate culture medium as described previously. Briefly, cells were plated in 12-well plates in normal growth medium. One or two days after plating, cells were contacted with increasing concentrations of a compound of Formula (I) for a period of 24 hours. Cell proliferation was determined by counting the cells using a Cell Coulter instrument (Beckman). As shown in Figures 3A-3B, contact with a compound of Formula (I) caused a sharp decrease in cell numbers within a narrow range of concentrations in human LNCaP prostate cancer cells (Figure 3A), human DU145 prostate cancer cells (Figure 3B), and in human PC3 prostate cancer cells (Figure 3C). The graphs represent residual cell viability expressed as a percent of control and are means ± SEM of at least 4 separate experiments, each performed in duplicate. Similar EC50 across cell lines was observed between about 2 and 3 μΜ. No significant difference was observed between cell lines, irrespective of their androgen sensitivity (androgen-dependent LNCaP or androgen-independent PC3 and DU145).
[0373] In addition to the human cell lines, mouse cell lines were also contacted with a compound of Formula (I). Cells were plated in 96-well plates in normal growth medium. The day after plating, cells were contacted with increasing concentrations of a compound of Formula (I) for a period of 24 hours. Cell viability was determined using the WST1 reagent. As shown in Figures 4A-4C, the compound of Formula (I) decreased cell viability in mouse prostate cell PTEN-P2 (Figure 4A) and PTEN-CAP2 (Figure 4B). ΡΊΈΝ- P2 and PTEN-CAP2 are two mouse isogenic cell lines that differ only by the presence or absence of the PTEN gene. Hence, PTEN-P2 express PTEN; whereas PTEN-CAP2 do not. The compound of Formula ( I ) has a similar effect in both cell lines, with an EC50 between 2 and 3 μΜ (similar to human prostate cancer cells). Results are expressed as percent of control and are means ± SEM of at least 5 independent experiments, each performed in triplicates. Figure 4C directly compares the effect of Formula (I) in the two cell lines to show the similarity of the dose-response.
[0374] As shown in Figures 5A-5D, docetaxel decreased the viability of prostate cancer cells to a limited extent. The effect of docetaxel after 24 hours of contact reached a plateau at a concentration of 0.1 μΜ and killed a maximum of 20% human prostate cancer cells DU145. The maximum effect of docetaxel differed between cell lines, killing about 40% of human PC3 cells and in mouse PTEN-P2 cells, with an EC50 in the range of 0.01 μΜ in most cell lines.
[0375] The combined effect of docetaxel and a compound of Formula (I) was examined in human PC3 cells and mouse PTEN-P2 cells. Figure 6 A shows that in PC3 cells, the combination was additive, and Figure 6B shows that in PTEN-P2 cells, the combination was supra-additive. Additivity is observed when the slopes of the trend lines are parallel (for example, the absolute values of the slopes are roughly the same). An increase in the absolute value of the slope indicates supra-additivity. Table 1 tabulates the slopes and coefficient of correlation obtained in several experiments performed in PTEN-P2 cells, and the effect of the combination. Taken together, the combination of docetaxel and Formula (I) showed additive cytotoxic effects in PTEN-P2 cells.
Table 1 : Additivity of Compound of Formula (I) and Taxane-Based Chemotherapy Agent
Figure imgf000110_0001
Example 2
In Vitro Effects of Compounds of Formula (I) on Bladder Cancer Cells
[0376] Bladder cancer cells were grown in their appropriate culture medium, such as, for example, DMEM containing 2mM L-glutamine, glucose (4.5g/ml), Glutamine, 10% FBS (Fetal Bovine Serum), 100 U/ml penicillin and 100 μg/ml streptomycin. The protein expression of androgen receptor (AR) and estrogen receptor (ER) in the bladder cancer cells of interest was assessed using Western blotting to establish or verify AR/ER status (positive or negative).
[0377] The cell response to DHT (androgen) and Estradiol (estrogen) was tested by contacting cells with the hormone of interest for several days and measuring cell proliferation/viability with the water soluble tetrazolium assay (2-(4-iodophenyl)-3-(4- nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium; "WST-1 assay"). In addition, cells were contacted with the hormone of interest for 24 hours and AR/ER protein levels were determined using Western-blotting. An increased rate of proliferation and increased AR/ER expression may be expected in AR-positive or ER-positive cells contacted with DHT or estradiol.
[0378] The effect of a composition including a compound of Formula (I) on AR and ER levels was measured by Western blot (protein levels) and qRT-PCR (mRNA levels) according to standard procedures. Compositions including a compound of Formula (I) may decrease AR levels, and also may decrease ER levels in ER-positive cells.
[0379] The effect of a composition including a compound of Formula (I) on the proliferation/viability of bladder cancer cells was assessed by contacting the cells with increasing concentrations of a compound of Formula (I) for 24 hours up to several days followed by the WST-1 assay. The dose corresponding to the ICso of a compound of Formula (I) was used in combination with increasing doses of an additional therapy, including androgen deprivation therapy, anti-estrogen therapy, a biologic, a virus-based therapy, surgery, chemotherapy (including taxane-based chemotherapy agents), antineoplastic agent (including platinum-based antineoplastic agents), radiation therapy, statin, repurposed drug therapy, small molecule inhibitor therapy, therapeutic antibody therapy, immunotherapy, or combinations thereof, optionally, wherein the chemotherapy or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy to measure cell proliferation/viability using the WST-1 assay.
[0380] In instances when the combination treatments revealed interference between the compound of Formula (I) and other drugs of interest, an Isobologram was performed to determine if the effect of the combination was additive, synergistic, or antagonist.
Example 3
Cytotoxicity of Compound of Formula (I) in Mouse Bladder Cancer Cells
[0381] The following example demonstrates the cytotoxicity of compounds of Formula (I) in mouse bladder cancer cell lines.
[0382] Mouse bladder cancer cells (MB49) were plated in 96-well plate the day before treatment. A composition including a compound of Formula (I) was added at increasing concentrations using serial dilutions from a stock solution. The control condition consisted of DMSO alone. Cells were incubated with a composition including a compound of Formula (I) for 24 hours at 37°C and 5% CO2 in normal cell growth conditions. As shown in Figures 7A-7C, the compound of Formula (I) decreased the viability of bladder cancer cells with an EC50 between 3 to 4 μΜ, and achieved complete toxicity at 6 μΜ, including in MB49 cells (Figure 7A), CRL1749 cells (Figure 7B), and HTB5 cells (Figure 7C). Results are expressed as percent of control and are means ± SEM of several independent experiments, each performed in triplicates.
Example 4
Effect of Combination of Chemotherapy Agents and a Compound of Formula (I) on
Cancer Cells
[0383] The following example demonstrates the efficacy of a product combination of chemotherapy agents, including cisplatin and valrubicin, in combination with a compound of Formula (I).
[0384] Cancer cells, including mouse MB49 cells or human CRL1749 bladder cancer cells, were plated in a 96-well plate the day before treatment and maintained in normal growth medium. A composition including valrubicin at varying concentrations, cisplatin at varying concentrations, a compound of Formula (I) at varying concentrations, a combination of valrubicin at varying concentration with a compound of Formula (I) at 2 μΜ, or a combination of cisplatin at 2 μΜ and a compound of Formula (I) at 1 μΜ was added to the cells. Cell viability was assessed using WST-1 reagent.
[0385] As shown in Figure 8A, valrubicin decreased the viability of prostate cancer cells to a maximum effect of 20% remaining viable cells (80% cells killed), reached at a concentration of 40 μΜ. ECso was in the range of 10 μΜ. Results are expressed as percent of control and are means ± SEM of 2 independent experiments, each performed in triplicates. Figure 8B depicts the results of cisplatin alone in MB49 cells. Figure 8C depicts the results of cisplatin in CRL1749 cells.
[0386] As shown in Figure 9, a composition with a compound of Formula (I) significantly decreased cell viability compared to control or cisplatin treatment alone. In addition, the combination of cisplatin with a compound of Formula (I) significantly decreased the viability of cancer cells compared to treatment a compound of Formula (I) alone or cisplatin alone. The cells were sensitive to the combination of cisplatin and a compound of Formula (I) to an extent that all cancer cells showed decreased viability, even at the lowest tested concentrations. In this experiment, the EC50 of cisplatin alone was about 40 μΜ, and the compound of Formula (I) was about 1 μΜ. The combination of cisplatin and a compound of Formula (I) decreased the EC50 for cisplatin to less than 2 μΜ.
[0387] A test experiment was performed to assess the combination effect of valrubicin and a compound of Formula (I) (Figure 10). In this example, the compound of Formula (I) was used in an amount of 2 μΜ, and was effective, killing 80% of the cells when used alone. The slope of the combination trend line was parallel to that of valrubicin alone, and indicates additivity (valrubicin alone = slope -16.13 and R2 0.99; valrubicin in combination with a compound of Formula (I) = slope -14.78 and R2 0.96).
Example 5
In Vivo Treatment of Bladder Cancer with Compound of Formula (I)
[0388] The mouse chamber model was used to assess the efficacy of a compound of Formula (I) alone or in combination in a clinically relevant model.
[0389] Mice are separated into several treatment groups: i) untreated (or sham- treated); ii) a compound of Formula (I) alone; iii) androgen deprivation therapy, anti- estrogen therapy, a biologic, a virus-based therapy, surgery, chemotherapy (including taxane- based chemotherapy agents), antineoplastic agent (including platinum-based antineoplastic agents), radiation therapy, statin, repurposed drug therapy, small molecule inhibitor therapy, therapeutic antibody therapy, immunotherapy, or combinations thereof, optionally, wherein the chemotherapy or antineoplastic agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy; and iv) combinations of a compound of Formula (I) with either modality or drug used in iii).
[0390] Tumor growth is measured by IVM as a function of time for several weeks as described in previous studies (Abedinpour et al. Prostate, 2013, 73, 489-499; Abedinpour et al. Prostate, 2011, 71, 813-823). Within subjects continuous variables are compared between groups using repeated measures ANOVA.
[0391] The effect on mouse overall survival of a compound of Formula (I) alone or in combination with the additional treatment of interest is evaluated by comparing the survival of mice treated with a compound of Formula (I) alone, the chemotherapy of interest alone, or in various combinations to the survival of mice treated with the standard of care therapy. These experiments are performed in the orthotopic mouse model of bladder cancer using transurethral cancer cell or in the BBN-treated model as described in the methods section here.
[0392] Animals are weighed and monitored regularly, and the end point for each animal is a 15% reduction in weight, overt signs of disease (as per IACUC guidelines), or tumor size (maximum 1 cm3) at which point the animals are euthanized and autopsied. Tumor weights are measured. A portion of each tumor is flash-frozen for Western blot and qPCR analysis. The remaining portion is fixed and processed for histological examination and immunohistochemistry (IHC). Tumor cell proliferation or apoptosis is estimated after sacrifice using common markers (such as Ki67 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay). Differences in survival between treatment groups is estimated and represented using Logrank tests and Kaplan-Meier plots.
[0393] It is to be understood that the description, specific examples and data, while indicating exemplary embodiments, are given by way of illustration and are not intended to limit the various embodiments of the present disclosure. Various changes and modifications within the present disclosure will become apparent to the skilled artisan from the description and data contained herein, and thus are considered part of the various embodiments of this disclosure.

Claims

WHAT IS CLAIMED IS:
1. A product combination for the inhibition or treatment of prostate cancer, wherein the product combination comprises:
a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000115_0001
wherein:
R1 is methyl;
R2 is hydrogen;
R3 is -OH;
R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen; and
a therapeutically effective amount of a taxane-based chemotherapy agent.
2. The product combination of claim 1, wherein the taxane-based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof.
3. The product combination of any one of claims 1-2, wherein the compound of Formula (I) is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts, and wherein the taxane-based chemotherapy agent is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ,
1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts.
4. The product combination of any one of claims 1-3, wherein said product combination inhibits the growth of prostate cancer.
5. The product combination of any one of claims 1-4, wherein said product combination inhibits or delays the onset of castration-resistant prostate cancer.
6. The product combination of any one of claims 1-5, wherein the compound of Formula (I) is formulated for oral or parenteral administration.
7. The product combination of any one of claims 1-6, wherein the taxane-based chemotherapy agent is formulated for oral or parenteral administration.
8. The product combination of any one of claims 1-7, wherein the compound of Formula (I) and the taxane-based chemotherapy agent are provided to a subject in a single formulation or a single dosage.
9. The product combination of any one of claims 1-8, wherein the compound of Formula (I) and the taxane-based chemotherapy agent are formulated for oral or parenteral administration.
10. The product combination of claim 1, wherein said prostate cancer is androgen dependent prostate cancer.
11. The product combination of claim 1, wherein said prostate cancer is castration-resistant prostate cancer.
12. The product combination of any one of claims 1-11, wherein the product combination reduces prostate cancer tumor size.
13. A method of inhibiting or treating prostate cancer, comprising administering to a subject having prostate cancer a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000117_0001
wherein:
R1 is methyl;
R2 is hydrogen;
R3 is -OH;
R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen; and
wherein the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a taxane-based chemotherapy agent; and wherein the prostate cancer is inhibited or treated.
14. The method of claim 13, wherein said method inhibits the growth of prostate cancer.
15. The method of any one of claims 13-14, wherein said method inhibits or delays the onset of castration-resistant prostate cancer.
16. The method of any one of claims 13-15, wherein the taxane-based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof.
17. The method of any one of claims 13-16, wherein the compound of Formula (I) is administered to the subject orally or parenterally.
18. The method of any one of claims 13-17, wherein the taxane-based chemotherapy agent is administered to the subject orally or parenterally.
19. The method of any one of claims 13-18, wherein the compound of Formula (I) and the taxane-based chemotherapy agent are administered to the subject orally or parenterally.
20. The method of claim 13, wherein said prostate cancer is androgen dependent prostate cancer.
21. The method of claim 13, wherein said prostate cancer is castration-resistant prostate cancer.
22. The method of any one of claims 13-21, wherein prostate cancer tumor size is reduced.
23. A product combination for the inhibition or treatment of prostate cancer, wherein the product combination comprises:
a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000118_0001
wherein:
R1 is methyl;
R2 is hydrogen;
R3 is -OH;
R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen; and
a therapeutically effective amount of a platinum-based antineoplastic agent.
24. The product combination of claim 23, wherein the platinum -based antineoplastic agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, or satraplatin, or analogues or derivatives thereof.
25. The product combination of any one of claims 23-24, wherein the compound of Formula (I) is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts and wherein the platinum-based antineoplastic agent is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts.
26. The product combination of any one of claims 23-25, wherein said product combination inhibits the growth of prostate cancer.
27. The product combination of any one of claims 23-26, wherein said product combination inhibits or delays the onset of castration-resistant prostate cancer.
28. The product combination of any one of claims 23-27, wherein the compound of Formula (I) is formulated for oral or parenteral administration.
29. The product combination of any one of claims 23-28, wherein the platinum- based antineoplastic agent is formulated for oral or parenteral administration.
30. The product combination of any one of claims 23-29, wherein the compound of Formula (I) and the platinum -based antineoplastic agent are provided to a subject in a single formulation or a single dosage.
31. The product combination of any one of claims 23-30, wherein the compound of Formula (I) and the platinum-based antineoplastic agent are formulated for oral or parenteral administration.
32. The product combination of claim 23, wherein said prostate cancer is androgen dependent prostate cancer.
33. The product combination of claim 23, wherein said prostate cancer is castration-resistant prostate cancer.
34. The product combination of any one of claims 23-33, wherein the product combination reduces prostate cancer tumor size.
35. A method of inhibiting or treating prostate cancer, comprising administering to a subject having prostate cancer a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000120_0001
wherein:
R1 is methyl;
R2 is hydrogen;
R3 is -OH;
R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen; and
wherein the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a platinum-based antineoplastic agent; and wherein the prostate cancer is inhibited or treated.
36. The method of claim 35, wherein said method inhibits the growth of prostate cancer.
37. The method of any one of claims 35-36, wherein said method inhibits or delays the onset of castration-resistant prostate cancer.
38. The method of any one of claims 35-37, wherein the platinum-based antineoplastic agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pynplatin, or satraplatin, or analogues or derivatives thereof.
39. The method of any one of claims 35-38, wherein the compound of Formula (I) is administered to the subject orally or parenterally.
40. The method of any one of claims 35-39, wherein the platinum-based antineoplastic agent is administered to the subject orally or parenterally.
41. The method of any one of claims 35-40, wherein the compound of Formula (I) and the platinum-based antineoplastic agent are administered to the subject orally or parenterally.
42. The method of claim 35, wherein said prostate cancer is androgen dependent prostate cancer.
43. The method of claim 35, wherein said prostate cancer is castration-resistant prostate cancer.
44. The method of any one of claims 35-43, wherein the prostate cancer tumor size is reduced.
45. A product combination that inhibits or delays the growth of bladder cancer, wherein the product combination comprises:
a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000121_0001
wherein:
R1 is methyl;
R2 is hydrogen;
R3 is -OH;
R4 is hydrogen;
R5 is hydrogen; R6 is hydrogen; and
a therapeutically effective amount of a taxane-based chemotherapy agent.
46. The product combination of claim 45, wherein the taxane-based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof.
47. The product combination of any one of claims 45 or 46, wherein the compound of Formula (I) is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts, and wherein the taxane-based chemotherapy agent is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts.
48. The product combination of any one of claims 45-47, wherein said product combination inhibits the growth of bladder cancer.
49. The product combination of any one of claims 45-48, wherein the compound of Formula (I) is formulated for oral or parenteral administration.
50. The product combination of any one of claims 45-49, wherein the taxane- based chemotherapy agent is formulated for oral or parenteral administration.
51. The product combination of any one of claims 45-50, wherein the compound of Formula (I) and the taxane-based chemotherapy agent are provided to a subject in a single formulation or a single dosage.
52. The product combination of any one of claims 45-51, wherein the compound of Formula (I) and the taxane-based chemotherapy agent are formulated for oral or parenteral administration.
53. The product combination of any one of claims 45-52, wherein the product combination reduces bladder cancer tumor size.
54. A method of inhibiting or delaying the growth of bladder cancer in a subject, comprising administering to a subject having bladder cancer a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000123_0001
wherein:
R1 is methyl;
R2 is hydrogen;
R3 is -OH;
R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen; and
wherein the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a taxane-based chemotherapy agent; and wherein the bladder cancer is inhibited or treated.
55. The method of claim 54, wherein the bladder cancer comprises transitional cell carcinoma, squamous cell carcinoma, and/or adenocarcinomas of the bladder.
56. The method of any one of claims 54-55, wherein said method inhibits the growth of bladder cancer.
57. The method of any one of claims 54-56, wherein said method inhibits or delays the onset of bladder cancer.
58. The method of any one of claims 54-57, wherein the taxane-based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof.
59. The method of any one of claims 54-58, wherein the compound of Formula (I) is administered to the subject orally or parenterally.
60. The method of any one of claims 54-59, wherein the taxane-based chemotherapy agent is administered to the subject orally or parenterally.
61. The method of any one of claims 54-60, wherein the compound of Formula (I) and the taxane-based chemotherapy agent are administered to the subject orally or parenterally.
62. The method of any one of claims 54-61, wherein bladder cancer tumor size is reduced.
63. A product combination for the inhibition or treatment of bladder cancer, wherein the product combination comprises:
a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000124_0001
wherein:
R1 is methyl;
R2 is hydrogen;
R3 is -OH;
R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen; and
a therapeutically effective amount of a platinum-based antineoplastic
64. The product combination of claim 63, wherein the platinum-based antineoplastic agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, or satraplatin, or analogues or derivatives thereof.
65. The product combination of any one of claims 63-64, wherein the compound of Formula (I) is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts and wherein the platinum-based antineoplastic agent is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts.
66. The product combination of any one of claims 63-65, wherein said product combination inhibits the growth of bladder cancer.
67. The product combination of any one of claims 63-66, wherein the compound of Formula (I) is formulated for oral or parenteral administration.
68. The product combination of any one of claims 63-67, wherein the platinum- based antineoplastic agent is formulated for oral or parenteral administration.
69. The product combination of any one of claims 63-68, wherein the compound of Formula (I) and the platinum -based antineoplastic agent are provided to a subject in a single formulation or a single dosage.
70. The product combination of any one of claims 63-69, wherein the compound of Formula (I) and the platinum-based antineoplastic agent are formulated for oral or parenteral administration.
71. The product combination of any one of claims 63-70, wherein the product combination reduces bladder cancer tumor size.
72. A method of inhibiting or delaying the growth of bladder cancer in a subject, comprising administering to a subject having bladder cancer a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000126_0001
wherein:
R1 is methyl;
R2 is hydrogen;
R3 is -OH;
R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen; and
wherein the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a platinum-based antineoplastic agent; and wherein the bladder cancer is inhibited or treated.
73. The method of claim 72, wherein the bladder cancer comprises transitional cell carcinoma, squamous cell carcinoma, and/or adenocarcinomas of the bladder.
74. The method of any one of claims 72-73, wherein said method inhibits the growth of bladder cancer.
75. The method of any one of claims 72-74, wherein said method inhibits or delays the onset of bladder cancer.
76. The method of any one of claims 72-75, wherein the platinum-based antineoplastic agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, or satraplatin, or analogues or derivatives thereof.
77. The method of any one of claims 72-76, wherein the compound of Formula (I) is administered to the subject orally or parenterally.
78. The method of any one of claims 72-77, wherein the platinum-based antineoplastic agent is administered to the subject orally or parenterally.
79. The method of any one of claims 72-78, wherein the compound of Formula (I) and the platinum-based antineoplastic agent are administered to the subject orally or parenterally.
80. The method of any one of claims 72-79, wherein the bladder cancer tumor size is reduced.
81. A product combination that inhibits or delays the growth or progression of bladder cancer, wherein the product combination comprises:
a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000127_0001
wherein:
R1 is methyl;
R2 is hydrogen;
R3 is -OH;
R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen; and
a therapeutically effective amount of a hormone deprivation agent.
82. The product combination of claim 81, wherein the hormone deprivation agent is an androgen deprivation agent or an estrogen deprivation agent.
83. The product combination of claim 82, wherein the androgen deprivation agent is orteronel, cyproterone acetate, flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, galeterone, abiraterone, finasteride, ethylstilbestrol (DES), megestrol acetate, fosfestrol, estramustine phosphate, leuprolide, triptorelin, goserelin, histrelin, buserelin, abarelix, degarelix, or derivatives, salts, or analogues thereof, or combinations thereof.
84. The product combination of claim 82, wherein the estrogen deprivation agent is tamoxifen, clomifene, ormeloxifene, toremifene, lasofoxifene, ospemifene, raloxifene, fulvestrant, brilanestrant, elacestrant, anastrozole, letrozole, testolactone, exemestane, or derivatives, salts, or analogues thereof, or combinations thereof.
85. The product combination of any one of claims 81-84, wherein the compound of Formula (I) is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts, and wherein the hormone deprivation agent is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts.
86. The product combination of any one of claims 81-85, wherein said product combination inhibits the growth or progression of bladder cancer.
87. The product combination of any one of claims 81-86, wherein the compound of Formula (I) is formulated for oral or parenteral administration.
88. The product combination of any one of claims 81-87, wherein the hormone deprivation agent is formulated for oral or parenteral administration.
89. The product combination of any one of claims 81-88, wherein the compound of Formula (I) and the hormone deprivation agent are provided to a subject in a single formulation or a single dosage.
90. The product combination of any one of claims 81-89, wherein the compound of Formula (I) and the hormone deprivation agent are formulated for oral or parenteral administration.
91. The product combination of any one of claims 81-90, wherein the product combination reduces bladder cancer tumor size.
92. A method of inhibiting or delaying the growth of bladder cancer in a subject, comprising optionally, selecting or identifying a subject as one having bladder cancer, and administering to said subject having bladder cancer a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000129_0001
wherein:
R1 is methyl;
R2 is hydrogen;
R3 is -OH;
R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen; and
wherein the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a hormone deprivation agent; and wherein the bladder cancer is inhibited or treated.
93. The method of claim 92, wherein the bladder cancer comprises transitional cell carcinoma, squamous cell carcinoma, and/or adenocarcinomas of the bladder.
94. The method of any one of claims 92-93, wherein said method inhibits the growth of bladder cancer.
95. The method of any one of claims 92-94, wherein said method inhibits or delays the onset of bladder cancer.
96. The method of any one of claims 92-95, wherein the hormone deprivation agent is an androgen deprivation agent or an anti-estrogen agent.
97. The method of claim 96, wherein the androgen deprivation agent is orteronel, cyproterone acetate, flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, galeterone, abiraterone, finasteride, ethylstilbestrol (DES), megestrol acetate, fosfestrol, estramustine phosphate, leuprolide, triptorelin, goserelin, histrelin, buserelin, abarelix, degarelix, or derivatives, salts, or analogues thereof, or combinations thereof.
98. The method of claim 96, wherein the anti-estrogen agent is tamoxifen, clomifene, ormeloxifene, toremifene, lasofoxifene, ospemifene, raloxifene, fulvestrant, brilanestrant, elacestrant, anastrozole, letrozole, testolactone, exemestane, or derivatives, salts, or analogues thereof, or combinations thereof.
99. The method of any one of claims 92-98, wherein the compound of Formula (I) is administered to the subject orally or parenterally.
100. The method of any one of claims 92-99, wherein the hormone deprivation agent is administered to the subject orally or parenterally.
101. The method of any one of claims 92-100, wherein the compound of Formula (I) and the hormone deprivation agent are administered to the subject orally or parenterally.
102. The method of any one of claims 92-101, wherein bladder cancer tumor size is reduced.
103. A product combination for the inhibition or treatment of cancer, wherein the product combination comprises:
a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000130_0001
R2 is hydrogen;
R3 is -OH;
R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen; and
a therapeutically effective amount of a chemotherapy agent, optionally, wherein the chemotherapy agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy.
104. The product combination of claim 103, wherein the chemotherapy agent is 5- fluorouracil, doxorubicin, gemcitabine, methotrexate, mitomycin C, valrubicin, or vinblastine, or analogues, derivatives, or combinations thereof.
105. The product combination of claim 103, wherein the chemotherapy agent is an antineoplastic agent or a taxane-based chemotherapy agent.
106. The product combination of claim 105, wherein the antineoplastic agent in a platinum-based antineoplastic agent selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, and satraplatin, or analogues or derivatives thereof.
107. The product combination of claim 105, wherein the taxane-based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof.
108. The product combination of any one of claims 103-107, wherein the compound of Formula (I) is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts and wherein the chemotherapy agent is present in an amount of 0.1 μΜ to 10 μΜ, such as 0.1 μΜ, 0.5 μΜ, 1.0 μΜ, 1.5 μΜ, 2 .0 μΜ, 2.5 μΜ, 3.0 μΜ, 3.5 μΜ, 4.0 μΜ, 4.5 μΜ, 5.0 μΜ, 5.5 μΜ, 6.0 μΜ, 6.5 μΜ, 7.0 μΜ, 7.5 μΜ, 8.0 μΜ, 8.5 μΜ, 9.0 μΜ, 9.5 μΜ, or 10.0 μΜ or within a range defined by any two of the aforementioned amounts.
109. The product combination of any one of claims 103-108, wherein said cancer is prostate cancer or bladder cancer.
110. The product combination of any one of claims 103-109, wherein said product combination inhibits the growth of bladder cancer or inhibits the growth of prostate cancer.
111. The product combination of any one of claims 103-110, wherein the compound of Formula (I) is formulated for oral or parenteral administration.
112. The product combination of any one of claims 103-111, wherein the chemotherapy agent is formulated for oral or parenteral administration.
113. The product combination of any one of claims 103-112, wherein the compound of Formula (I) and the chemotherapy agent are provided to a subject in a single formulation or a single dosage.
114. The product combination of any one of claims 103-113, wherein the compound of Formula (I) and the chemotherapy agent are formulated for oral or parenteral administration.
115. The product combination of any one of claims 103-114, wherein the product combination reduces bladder cancer tumor size or reduces prostate cancer tumor size.
116. A method of inhibiting or delaying the growth of cancer in a subject, comprising administering to a subject having cancer a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):
Figure imgf000132_0001
wherein:
R1 is methyl;
R2 is hydrogen;
R3 is -OH; R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen; and
wherein the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, a therapeutically effective amount of a chemotherapy agent, optionally, wherein the chemotherapy agent is not a hormonal therapy, is not a hormone replacement therapy, is not a hormone deprivation therapy, is not an androgen deprivation therapy, or is not an anti-estrogen therapy; and wherein the cancer is inhibited or treated.
117. The method of claim 116, wherein the chemotherapy agent is 5-fluorouracil, doxorubicin, gemcitabine, methotrexate, mitomycin C, valrubicin, or vinblastine, or analogues, derivatives, or combinations thereof.
118. The method of claim 116, wherein the chemotherapy agent is an antineoplastic agent or a taxane-based chemotherapy agent.
119. The method of claim 118, wherein the antineoplastic agent in a platinum- based antineoplastic agent selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, ormaplatin, phenanthriplatin, picoplatin, pyriplatin, and satraplatin, or analogues or derivatives thereof.
120. The method of claim 118, wherein the taxane-based chemotherapy agent is docetaxel, paclitaxel, cabazitaxel, larotaxel, ortataxel, milataxel, tesetaxel, or abraxane, or analogues, derivatives, emulsions, pro-drugs, or lipid conjugates, or polymers thereof.
121. The method of any one of claims 116-120, wherein the cancer is bladder cancer or prostate cancer.
122. The method of claim 121, wherein the bladder cancer comprises transitional cell carcinoma, squamous cell carcinoma, and/or adenocarcinomas of the bladder.
123. The method of any one of claims 121-122, wherein said method inhibits the growth of bladder cancer or inhibits the growth or prostate cancer.
124. The method of any one of claims 121-123, wherein said method inhibits or delays the onset of bladder cancer or inhibits or delays the onset of prostate cancer.
125. The method of any one of claims 116-124, wherein the compound of Formula (I) is administered to the subject orally or parenterally.
126. The method of any one of claims 116-125, wherein the chemotherapy agent is administered to the subject orally or parenterally.
127. The method of any one of claims 116-126, wherein the compound of Formula (I) and the chemotherapy agent are administered to the subject orally or parenterally.
128. The method of any one of claims 121-127, wherein a size of a bladder cancer tumor or a size of a prostate cancer tumor is reduced.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130219528A1 (en) * 2010-08-04 2013-08-22 Pellficure Pharmaceuticals, Inc. Novel treatment of prostate carcinoma
US20150233927A1 (en) * 2012-09-19 2015-08-20 Cornell University Identifying taxane sensitivity in prostate cancer patients

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130219528A1 (en) * 2010-08-04 2013-08-22 Pellficure Pharmaceuticals, Inc. Novel treatment of prostate carcinoma
US20150352060A1 (en) * 2010-08-04 2015-12-10 Pellficure Pharmaceuticals, Inc. Novel treatment of prostate carcinoma
US20150233927A1 (en) * 2012-09-19 2015-08-20 Cornell University Identifying taxane sensitivity in prostate cancer patients

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