WO2020139943A1 - Inhibiteurs de la signalisation de l'ezh2 et d'un récepteur d'androgènes en tant qu'outils pour le ciblage du cancer de la prostate - Google Patents

Inhibiteurs de la signalisation de l'ezh2 et d'un récepteur d'androgènes en tant qu'outils pour le ciblage du cancer de la prostate Download PDF

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Publication number
WO2020139943A1
WO2020139943A1 PCT/US2019/068575 US2019068575W WO2020139943A1 WO 2020139943 A1 WO2020139943 A1 WO 2020139943A1 US 2019068575 W US2019068575 W US 2019068575W WO 2020139943 A1 WO2020139943 A1 WO 2020139943A1
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grams
pharmaceutically acceptable
acceptable salt
effective amount
therapeutically effective
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PCT/US2019/068575
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English (en)
Inventor
John Mcgrath
Adrian SENDEROWICZ
Patrick Trojer
William D. Bradley
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Constellation Pharmaceuticals, Inc.
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Publication of WO2020139943A1 publication Critical patent/WO2020139943A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • prostate cancer is the second most common type of cancer amongst men in the United States and is the second leading cause of cancer death in this population.
  • the growth and survival of prostate cancer cells depend primarily on the androgen receptor signaling pathway. Cancer cells can use the binding of androgens to androgen receptors to trigger abnormal cell growth and tumor progression.
  • ADT androgen deprivation therapy
  • Medical castration involves gonadotropin-releasing hormone antagonists, alone or in combination with first generation anti-androgen therapy.
  • Most men with prostate cancer treated with ADT respond, as measured by tumor regression, relief of symptoms and reductions in serum prostate-specific antigen, or PSA, level and are considered to have hormone-sensitive prostate cancer.
  • CRPC castration-resistant prostate cancer
  • Castration-resistant prostate cancer that spreads, or metastasizes, to other parts of the body is diagnosed as mCRPC and may be characterized by increasing PSA levels, elevated circulating tumor cell (CTC) counts and soft tissue disease. Elevated CTC counts have been demonstrated to be a poor prognostic factor for overall survival in patients with mCRPC. See e.g., Int. J. Mol Sci. 2016, 17(9), 1580. CTCs are cells that have shed from a primary tumor and are carried around the body in the blood and may lead to metastases. A 30% decline in CTC counts as early as four weeks after treatment initiation suggests that advanced prostate cancer patients may benefit from treatment.
  • mCRPC patients with mCRPC have an average survival of approximately 30 months and experience a deterioration in quality of life despite treatment with the available therapeutic options.
  • the current standard of practice is to treat mCRPC with a second generation androgen receptor signaling (ARS) inhibitor, such as abiraterone acetate or enzalutamide.
  • ARS second generation androgen receptor signaling
  • Such products are approved in the United States for first-line therapy in chemotherapy-naive patients with mCRPC as well as for second-line treatment in patients who have received prior chemotherapy.
  • Compound 1 and enzalutamide experienced a reduction in CTC levels of more than 30% from baseline; and two (2) out of two (2) patients being dosed with Compound 1 and enzalutamide had resolution of metastatic disease. See e.g., FIG. 5, FIG. 6, and the
  • compositions comprising Compound 1, or a pharmaceutically acceptable salt thereof, and an ARSI such as enzalutamide, abiraterone, or abiraterone/prednisone.
  • an ARSI such as enzalutamide, abiraterone, or abiraterone/prednisone for treating prostate cancer.
  • pharmaceutical compositions comprising Compound 1, or a pharmaceutically acceptable salt thereof, and an ARSI such as enzalutamide, abiraterone, or abiraterone/prednisone.
  • FIG. 1 illustrates the in vitro synergistic results on cell viability in the LNCaP prostate cancer cell line using Compound 1 and the ARSI enzalutamide.
  • CPI- 1205 is Compound 1.
  • FIG. 2 shows the in vitro effects of Compound 1 with enzalutamide or abiraterone in various prostate cancer cells lines.
  • CPI- 1205 is Compound 1.
  • FIG. 3 shows the in vivo efficacy of Compound 1 with enzalutamide in a mouse xenograft prostate tumor model.
  • CPI- 1205 is Compound 1.
  • FIG. 4 is an illustration of the human patient population in a clinical trial by treatment protocol and duration.
  • CP-1205 and CPI-1205 are Compound 1.
  • FIG. 5 shows the evolution of PSA changes for each evaluable patient in a clinical trial treated with Compound 1 and enzalutamide or abiraterone, beginning with the pre-screening period (prior to treatment).
  • CPI- 1205 is Compound 1.
  • FIG. 6 depicts the change in CTC count in four patients in a clinical trial, using Compound 1 and enzalutamide or abiraterone, who had unfavorable CTC counts at baseline and have had at least one post-baseline CTC measurement.
  • FIG. 7 shows the PSA reduction in a patient who was treated and refractory to numerous therapies prior to the administration of Compound 1 and enzalutamide.
  • CPI- 1205 is Compound 1.
  • FIG. 8 shows results from a PET/CT scan following 1 month treatment with Compound 1 and enzalutamide, followed by monotherapy with Compound 1.
  • FIG. 9. shows results from a PET/CT scan following 1 month treatment with Compound 1 and enzalutamide, followed by monotherapy with Compound 1.
  • ARSI enzalutamide, abiraterone, or
  • compositions comprising Compound 1, or a pharmaceutically acceptable salt thereof, and an ARSI such as enzalutamide, abiraterone, or abiraterone/prednisone.
  • pharmaceutically acceptable carrier refers to a non-toxic carrier, adjuvant, or vehicle that does not adversely affect the pharmacological activity of the compound with which it is formulated, and which is also safe for human use.
  • compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, magnesium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose, lactose monohydrate, sodium lauryl sulfate, and crosscarmellose sodium), polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,
  • Pharmaceutically acceptable salt forms of Compound 1 and/or the androgen receptor signaling inhibitor include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • Suitable pharmaceutically acceptable basic/cationic salts include e.g., the sodium, potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine salts.
  • Pharmaceutically acceptable acid addition salts include e.g., salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids).
  • inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids
  • organic acids such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids.
  • treatment refers to reversing, alleviating, or inhibiting the progress of prostate cancer, or one or more symptoms thereof.
  • the term“effective amount” or“therapeutically effective amount” refers to an amount of a compound described herein that will elicit a biological or medical response of a subject e.g., a dosage of between 0.001 - 100 mg/kg body weight/day.
  • the term“patient,” as used herein, means an animal, such as a mammal, and such as a human.
  • the terms“subject” and“patient” may be used interchangeably.
  • compositions and method of administration herein may be orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra- synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions described herein are formulated for oral administration.
  • a subject who is characterized as progressed or relapsed is one who at one time responded to a given treatment such as an androgen receptor signaling inhibitor, a steroid, a pharmacological inhibitor of the enzyme poly ADP ribose polymerase (PARP), a tyrosine kinase inhibitor, a checkpoint inhibitor, radium 223, radiotherapy, chemotherapy, a CYP17A inhibitor, a steroid, or a VEGF inhibitor, but who no longer responds.
  • a given treatment such as an androgen receptor signaling inhibitor, a steroid, a pharmacological inhibitor of the enzyme poly ADP ribose polymerase (PARP), a tyrosine kinase inhibitor, a checkpoint inhibitor, radium 223, radiotherapy, chemotherapy, a CYP17A inhibitor, a steroid, or a VEGF inhibitor, but who no longer responds.
  • PARP poly ADP ribose polymerase
  • a subject who is characterized as refractory or resistant is one who is unresponsive or demonstrates worsening of disease while on a given treatment such as an androgen receptor signaling inhibitor, a steroid, a pharmacological inhibitor of the enzyme poly ADP ribose polymerase (PARP), a tyrosine kinase inhibitor, a checkpoint inhibitor, radium 223, radiotherapy, chemotherapy, a CYP17A inhibitor, a steroid, or a VEGF inhibitor.
  • PARP poly ADP ribose polymerase
  • kits for treating prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of (R)-N- ((4-methoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-methyl-l-(l-(l-(2,2,2- trifluoroethyl)piperidin-4-yl)ethyl)-lH-indole-3-carboxamide, or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an androgen receptor signaling inhibitor, or a pharmaceutically acceptable salt thereof.
  • compositions comprising a therapeutically effective amount of (R)-N-((4-methoxy-6-methyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)-2-methyl- 1 -( 1 -( 1 -(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)- 1H- indole-3-carboxamide, or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an androgen receptor signaling inhibitor, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a therapeutically effective amount of (R)-N-((4-methoxy-6-methyl-2-oxo-l,2-dihydropyridin- 3-yl)methyl)-2-methyl-l-(l-(l-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-lH-indole-3- carboxamide, or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an androgen receptor signaling inhibitor, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier for treating prostate cancer.
  • a therapeutically effective amount of Compound 1 may be administered prior to, concurrently with, or after administration of the androgen receptor signaling inhibitor.
  • simultaneous administration is not necessary for therapeutic purposes.
  • Compound 1 e.g., as described in any one of the first to third and fifth embodiments
  • the subject described herein e.g., as described in any one of the first to third and fifth embodiments
  • the androgen receptor signaling inhibitor i.e., Compound 1 is administered after the androgen receptor signaling inhibitor
  • a period of time such as e.g., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, or 6.0 hours or greater before Compound 1 is administered to the subject.
  • exemplary types of prostate cancer treated by the methods and uses described herein include e.g., acinar adenocarcinoma, ductal adenocarcinoma, transitional cell cancer, squamous cell cancer, small cell prostate cancer, and castration resistant prostate cancer (CRPC).
  • the prostate cancer to be treated by the methods and uses described herein is mCRPC.
  • the therapeutically effective amount of Compound 1 and/or the androgen receptor signaling inhibitor that is administered to a subject, or the effective amount of Compound 1 and/or the androgen receptor signaling inhibitor that is formulated in a provided composition is such that a dosage of between 0.01 - 100 mg/kg body weight/day can be administered to the subject. It will be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the cancer being treated.
  • the therapeutically effective amount of Compound 1 described in the methods and uses herein ranges from 50 mg to 3.5 grams administered once, twice, or three times a day, e.g., from 100 mg to 3.5 grams, from 200 mg to 3.0 grams, from 200 mg to 2.5 grams, from 200 mg to 1.0 grams, from 200 mg to 1.5 grams, from 200 mg to 1 gram, from 300 mg to 800 mg, from 400 mg to 800 mg, or from 400 mg to 600 mg administered once, twice, or three times a day.
  • the therapeutically effective amount of Compound 1 described in the methods and uses herein ranges from 100 mg to 3.5 grams, from 200 mg to 3.0 grams, from 200 mg to 2.5 grams, from 200 mg to 1.0 grams, from 200 mg to 1.5 grams, from 200 mg to 1 gram, from 300 mg to 800 mg, from 400 mg to 800 mg, from 400 mg to 600 mg, from 1.0 grams to 2.0 grams, from 1.4 grams to 1.7 grams, from 500 mg to 700 mg, from 550 mg to 650 mg, from 700 mg to 900 mg, from 750 mg to 850 mg, from 300 mg to 500 mg, or from 350 mg to 450 mg administered once, twice, or three times a day.
  • the therapeutically effective amount of Compound 1 described in the methods and uses herein is 3.5 grams, 3.4 grams, 3.3 grams, 3.2 grams, 3.1 grams, 3.0 grams, 2.9 grams, 2.8 grams, 2.7 grams, 2.6 grams, 2.5 grams, 2.4 grams, 2.3 grams, 2.2 grams, 2.1 grams, 2.0 grams, 1.9 grams, 1.8 grams, 1.7 grams, 1.6 grams, 1.5 grams, 1.4 grams, 1.3 grams, 1.2 grams, 1.1 grams, 1.0 grams, 900 mg, 800 mg, 700 mg, 600 mg, 500 mg, 400 mg, or 300 mg administered once, twice, or three times a day.
  • the therapeutically effective amount of Compound 1 described in the methods and uses herein is 3.2 grams, 2.4 grams, 1.6 grams, 1.2 grams, 800 mg administered once, twice, or three times a day.
  • the therapeutically effective amount of Compound 1 described in the methods and uses herein is 1.6 grams administered twice a day, 800 mg administered three times a day, 800 mg administered twice a day, 600 mg administered twice a day, or 400 mg administered twice a day.
  • the therapeutically effective amount of Compound 1 described in the methods and uses herein is 800 mg administered three times a day.
  • Compositions described herein e.g., as in the fourth embodiment
  • the androgen receptor signaling inhibitor in the methods, uses, and compositions herein is selected from enzalutamide, abiraterone acetate, bicalutamide, apalutamide, darolutamide, or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of the androgen receptor signaling inhibitor in the methods and uses herein ranges from 10 mg to 4.0 grams, e.g., from 50 mg to 3.0 grams, from 100 mg to 3.0 grams, from 500 mg to 2.5 grams, from 500 mg to 2.0 grams, from 500 mg to 1.5 grams, from 750 mg to 1.5 grams, from 50 mg to 1.0 gram, from 50 mg to 500 mg, from 50 mg to 300 mg, from 50 mg to 200 mg, or from 100 mg to 200 mg.
  • Compositions described herein may be formulated with an amount or range for an androgen receptor signaling inhibitor as described in this tenth embodiment.
  • the androgen receptor signaling inhibitor in the methods and uses herein (e.g., as in any one of the first to tenth embodiments) is
  • the androgen receptor signaling inhibitor in the methods and uses herein is enzalutamide, or a pharmaceutically acceptable salt thereof in an amount ranging from 50 mg to 1.0 gram, from 50 mg to 500 mg, from 50 mg to 300 mg, from 50 mg to 200 mg, or from 100 mg to 200 mg.
  • the androgen receptor signaling inhibitor in the methods and uses herein is enzalutamide, or a pharmaceutically acceptable salt thereof in an amount ranging from 50 mg to 1.0 gram, from 50 mg to 500 mg, from 50 mg to 300 mg, from 50 mg to 200 mg, or from 100 mg to 200 mg.
  • the androgen receptor signaling inhibitor in the methods and uses herein is e.g., as in any one of the first to tenth embodiments.
  • compositions described herein may be formulated with an amount or range for enzalutamide as described in this twelfth embodiment.
  • the androgen receptor signaling inhibitor in the methods and uses herein is abiraterone acetate.
  • the androgen receptor signaling inhibitor in the methods and uses herein is abiraterone acetate in an amount ranging from 100 mg to 3.0 grams, from 500 mg to 2.5 grams, from 500 mg to 2.0 grams, from 500 mg to 1.5 grams, or from 750 mg to 1.5 grams.
  • the androgen receptor signaling inhibitor in the methods and uses herein is abiraterone acetate ranging in amount from 900 mg to 1.1 grams.
  • Compositions described herein (e.g., as in the fourth and eighth embodiment) may be formulated with an amount or range for abiraterone acetate as described in this fourteenth embodiment.
  • the androgen receptor signaling inhibitor abiraterone acetate (e.g., as described in the fourteenth embodiment) is combined with a therapeutically effective amount of prednisone, or a pharmaceutically acceptable salt thereof.
  • the disclosed methods and compositions e.g., as in any one of the first to fourteenth
  • the therapeutically effective amount of prednisone, or pharmaceutically acceptable salt thereof ranges from 1 mg to 10 mg, from 1 mg to 8 mg, from 2 mg to 8 mg, from 3 mg to 7 mg, or from 4 mg to 6 mg.
  • a subject treated by the methods and uses described herein are characterized as progressed or relapsed to a disclosed androgen receptor signaling inhibitor, a steroid, a pharmacological inhibitor of the enzyme poly ADP ribose polymerase (PARP), a tyrosine kinase inhibitor, a checkpoint inhibitor, radium 223, radiotherapy, chemotherapy, a CYP17A inhibitor, a steroid, or a VEGF inhibitor.
  • PARP poly ADP ribose polymerase
  • a subject treated by the methods and uses described herein are characterized as progressed or relapsed to chemotherapy, PARP inhibitors, tyrosine kinase inhibitors, checkpoint inhibitors, radium 223, or radiotherapy.
  • a subject treated by the methods and uses described herein are characterized as progressed or relapsed to a disclosed androgen receptor signaling inhibitor (e.g., enzalutamide, abiraterone acetate, and abiraterone
  • a subject treated by the methods and uses described herein is characterized as refractory or resistant to a disclosed androgen receptor signaling inhibitor, a steroid, a pharmacological Inhibitor of the enzyme poly ADP ribose polymerase (PARP), a tyrosine kinase inhibitor, a checkpoint inhibitor, radium 223, radiotherapy, chemotherapy, a CYP17A inhibitor, a steroid, or a VEGF inhibitor.
  • PARP poly ADP ribose polymerase
  • a subject treated by the methods and uses described herein is characterized as refractory or resistant to chemotherapy, PARP inhibitors, tyrosine kinase inhibitors, checkpoint inhibitors, radium 223, or radiotherapy.
  • a subject treated by the methods and uses described herein is characterized as refractory or resistant to chemotherapy, PARP inhibitors, tyrosine kinase inhibitors, checkpoint inhibitors, radium 223, or radiotherapy.
  • a subject treated by the methods and uses described herein is characterized as refractory or resistant to chemotherapy, PARP inhibitors, tyrosine kinase inhibitors, checkpoint inhibitors, radium 223, or radiotherapy.
  • a disclosed androgen receptor signaling inhibitor e.g., enzalutamide, abiraterone acetate, and abiraterone acetate/prednisone.
  • the methods, uses, and compositions described herein further comprise the addition of a therapeutically effective amount of cobicistat, or a pharmaceutically acceptable salt thereof.
  • (R)-N-((4-methoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-methyl-l- (l-(l-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-lH-indole-3-carboxamide can be made according to the procedure set forth in U.S. Patent No. 9,085,583, the contents of which are incorporated herein by reference.
  • Relative cell viability percentage at each time point was calculated by dividing the RLU of each experimental condition by the RLU of the DMSO-treated control on the same plate, then multiplied by 100.
  • the mean value plus or minus the standard error of the mean from triplicate plates were plotted versus concentration of either drug, and non-linear regression used to generate curve and extrapolate the 50% growth inhibition value (GI50).
  • GI50 50% growth inhibition value
  • FIG. 1 Representative results are shown by FIG. 1. As shown, LNCaP cell viability was impacted by either Compound 1 or the ARSI enzalutamide, with co-treatment of Compound 1 and the ARSI enzalutamide resulting in synergistic inhibition of cell viability.
  • FIG. 4 presents the duration of treatment for each of the ten patients treated in the trial.
  • FIG. 5 shows the evolution of PSA changes for each evaluable patient treated in the trial beginning with the pre-screening period (prior to treatment).
  • One patient did not have a PSA measurement at baseline and is not included in the figure below.
  • FIG. 6 depicts the change in CTC counts in the four patients in the trial who had unfavorable CTC counts at baseline and had at least one post-baseline CTC measurement. Each of these patients have been treated in the enzalutamide arm. As in FIG. 6, two of these patients have experienced a reduction in CTC count of more than 30% from baseline.

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Abstract

L'invention concerne des méthodes d'utilisation du (R)-N-((4-méthoxy-6-méthyl-2-oxo-1,2-dihydropyridin-3-yl)méthyl)-2-méthyl-1-(1-(1-(2,2,2-trifluoroéthyl)pipéridin-4-yl)éthyl)-1H-indole-3-carboxamide, ou un sel pharmaceutiquement acceptable de celui-ci et d'un inhibiteur de signalisation d'un récepteur d'androgènes pour le traitement du cancer de la prostate. L'invention concerne également des compositions pharmaceutiques comprenant du (R)-N-((4-méthoxy-6-méthyl-2-oxo-1,2-dihydropyridin-3-yl)méthyl)-2- méthyl- 1-( 1-( 1-(2, 2, 2-trifluoroéthyl)pipéridin-4-yl)éthyl)-1H- indole-3-carboxamide, ou un sel pharmaceutiquement acceptable de celui-ci et un inhibiteur de signalisation d'un récepteur d'androgènes.
PCT/US2019/068575 2018-12-27 2019-12-26 Inhibiteurs de la signalisation de l'ezh2 et d'un récepteur d'androgènes en tant qu'outils pour le ciblage du cancer de la prostate WO2020139943A1 (fr)

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PCT/US2019/068575 WO2020139943A1 (fr) 2018-12-27 2019-12-26 Inhibiteurs de la signalisation de l'ezh2 et d'un récepteur d'androgènes en tant qu'outils pour le ciblage du cancer de la prostate

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013075084A1 (fr) 2011-11-18 2013-05-23 Constellation Pharmaceuticals Modulateurs d'enzymes de modification par méthylation, compositions et utilisations associées
WO2013075083A1 (fr) 2011-11-18 2013-05-23 Constellation Pharmaceuticals Modulateurs d'enzymes de modification par méthylation, compositions et utilisations associées
WO2013078320A1 (fr) 2011-11-21 2013-05-30 Constellation Pharmaceuticals Modulateurs d'enzymes de modification par méthylation, compositions et utilisations associées
WO2013120104A2 (fr) 2012-02-10 2013-08-15 Constellation Pharmaceuticals Modulateurs d'enzymes de modification par méthylation, leurs compositions et utilisations
WO2014124418A1 (fr) 2013-02-11 2014-08-14 Constellation Pharmaceuticals, Inc. Modulateurs d'enzymes de modification par méthylation, compositions et utilisations associées
WO2014151142A1 (fr) 2013-03-15 2014-09-25 Constellation Pharmaceuticals, Inc. Modulateurs d'enzymes de modification du méthyle, compositions et utilisations associées
WO2015023915A1 (fr) 2013-08-15 2015-02-19 Constellation Pharmaceuticals, Inc. Dérivés d'indole utilisés en tant que modulateurs d'enzymes de modification du méthyle, compositions et utilisations associées
WO2018136596A1 (fr) * 2017-01-20 2018-07-26 Constellation Pharmaceuticals, Inc. Dispersions solides de (r)-n-((4-méthoxy-6-méthyl-2-oxo-1,2-dihydropyridin-3-yl)méthyl)-2-méthyl-1-(1-(1-(2,2,2-trifluoroéthyl)pipéridin-4-yl)éthyl)-1h-indole-3-carboxamide
US20180296574A1 (en) * 2017-04-13 2018-10-18 Janssen Pharmaceutica Nv Combination Therapy for Prostate Cancer

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013075084A1 (fr) 2011-11-18 2013-05-23 Constellation Pharmaceuticals Modulateurs d'enzymes de modification par méthylation, compositions et utilisations associées
WO2013075083A1 (fr) 2011-11-18 2013-05-23 Constellation Pharmaceuticals Modulateurs d'enzymes de modification par méthylation, compositions et utilisations associées
WO2013078320A1 (fr) 2011-11-21 2013-05-30 Constellation Pharmaceuticals Modulateurs d'enzymes de modification par méthylation, compositions et utilisations associées
WO2013120104A2 (fr) 2012-02-10 2013-08-15 Constellation Pharmaceuticals Modulateurs d'enzymes de modification par méthylation, leurs compositions et utilisations
US9085583B2 (en) 2012-02-10 2015-07-21 Constellation—Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
WO2014124418A1 (fr) 2013-02-11 2014-08-14 Constellation Pharmaceuticals, Inc. Modulateurs d'enzymes de modification par méthylation, compositions et utilisations associées
WO2014151142A1 (fr) 2013-03-15 2014-09-25 Constellation Pharmaceuticals, Inc. Modulateurs d'enzymes de modification du méthyle, compositions et utilisations associées
WO2015023915A1 (fr) 2013-08-15 2015-02-19 Constellation Pharmaceuticals, Inc. Dérivés d'indole utilisés en tant que modulateurs d'enzymes de modification du méthyle, compositions et utilisations associées
WO2018136596A1 (fr) * 2017-01-20 2018-07-26 Constellation Pharmaceuticals, Inc. Dispersions solides de (r)-n-((4-méthoxy-6-méthyl-2-oxo-1,2-dihydropyridin-3-yl)méthyl)-2-méthyl-1-(1-(1-(2,2,2-trifluoroéthyl)pipéridin-4-yl)éthyl)-1h-indole-3-carboxamide
US20180296574A1 (en) * 2017-04-13 2018-10-18 Janssen Pharmaceutica Nv Combination Therapy for Prostate Cancer

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
INT. J. MOL. SCI., vol. 17, no. 9, 2016, pages 1580
TAPLIN M-E ET AL: "A phase 1b/2 study of CPI-1205, a small molecule inhibitor of EZH2, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration resistant prostate cancer (mCRPC)", EMBASE, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, 1 February 2018 (2018-02-01), XP002788198 *
XIAO LANBO ET AL: "Epigenetic Reprogramming with Antisense Oligonucleotides Enhances the Effectiveness of Androgen Receptor Inhibition in Castration-Resistant Prostate Cancer", CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, AACR ANNUAL MEETING 2018; APRIL 14-18, 2018; CHICAGO, IL, vol. 78, no. 20, 15 October 2018 (2018-10-15), pages 5731 - 5740, XP002788199, ISSN: 1538-7445, DOI: 10.1158/0008-5472.CAN-18-0941 *

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