WO2020205608A1 - Utilisations d'antagonistes du récepteur des androgènes et d'inhibiteurs de la voie jnk et compositions pharmaceutiques associées - Google Patents

Utilisations d'antagonistes du récepteur des androgènes et d'inhibiteurs de la voie jnk et compositions pharmaceutiques associées Download PDF

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WO2020205608A1
WO2020205608A1 PCT/US2020/025439 US2020025439W WO2020205608A1 WO 2020205608 A1 WO2020205608 A1 WO 2020205608A1 US 2020025439 W US2020025439 W US 2020025439W WO 2020205608 A1 WO2020205608 A1 WO 2020205608A1
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certain embodiments
cancer
subject
androgen receptor
prostate cancer
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PCT/US2020/025439
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English (en)
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Carlos Sanchez MORENO
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Emory University
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    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • Prostate cancer is commonly identified based on rising serum prostate specific antigen (PSA) levels followed by a biopsy. Once diagnosed, prostate gland removal, radiation, and treatment with hormone-lowering drugs is typical. Androgen deprivation therapy (ADT) is often use for patients with advanced and metastatic prostate cancer. Patients usually respond favorably but may experience disease progression which is referred to as castration-resistant prostate cancer (CRPC). Thus, there is a need to identify improved methods of managing prostate cancer.
  • PSA prostate specific antigen
  • ADT Androgen deprivation therapy
  • CRPC castration-resistant prostate cancer
  • This disclosure relates to methods of treating or preventing cancer and pharmaceutical compositions related thereto. In certain embodiments, this disclosure relates to methods of treating cancer by administering an androgen deprivation therapy in combination with the JNK pathway. In certain embodiments, this disclosure relates to methods of treating cancer comprising administering an effective amount of an androgen receptor antagonist or androgen synthesis pathway inhibitor in combination with a JNK pathway inhibitor to a subject in need thereof.
  • androgen receptor antagonist is enzalutamide.
  • the JNK pathway inhibitor is bentamapimod.
  • the androgen synthesis pathway inhibitor is abiraterone.
  • the cancer is prostate cancer.
  • the disclosure relates to a method of treating cancer comprising administering an effective amount of enzalutamide in combination with bentamapimod to a subject in need thereof.
  • the disclosure relates to a method of treating cancer comprising administering an effective amount of abiraterone in combination with bentamapimod to a subject in need thereof.
  • the subject is a human. In certain embodiments, the subject is diagnosed with castration resistant prostate cancer. In certain embodiments, the subject is diagnosed with nonmetastatic castration-resistant prostate cancer. In certain embodiments, the subject is diagnosed with metastatic castration-resistant prostate cancer.
  • this disclosure relates to pharmaceutical compositions comprising an androgen receptor antagonist or androgen synthesis pathway inhibitor in combination with a JNK pathway inhibitor and a pharmaceutically acceptable excipient.
  • the androgen receptor antagonist is enzalutamide.
  • FIG 1 illustrates the chemical structure of bentamapimod (JNK Inhibitor AS602801).
  • Figure 2A shows data on the effect of Enzalutamide and AS602801.
  • LNCaP cells were plated 10,000 cells/well in 96-well plates and treated with ENZ, AS602801, or both and cell viability was assessed using RealTime GloTM MT Cell Viability Assay.
  • FIG. 2B shows data for C4-2 cells.
  • Figure 2C shows data on the proliferation of LNCaP cells was assayed by MTT at the indicated concentrations over a 5-day time course.
  • Figure 2D shows data on cell death of LNCaP cells after 48 hr incubation with ENZ (12.5mM), AS602801 (7.5mM), or both was measured using CellTox Green® assay, indicating strong synergy with the combination.
  • Figure 3 A shows data indicating AS602801 synergizes with ENZ to inhibit LNCaP cell invasion and destabilizes AR protein.
  • LNCaP cells were seeded in the upper chamber of a 24-well transwell at lxlO 5 cells per well treated with DMSO 0.1 % (control); enzalutamide (12.5mM); AS602801 (7.5mM); or the combination for 24 hours. Invaded cells were imaged and counted using Fiji.
  • Figure 3B shows data with C4-2B cells.
  • Figure 3C shows data of quantification of PSA.
  • GAP DH was used as loading control.
  • LNCaP cells were seeded for 24h and treated with indicated concentrations for 48h for PSA and AR detection.
  • For p-Erk detection LNCaP cells were pretreated with 5ug/ml EGF for 1 h after 24h serum starvation, and then treated with indicated drug concentration for 1 h.
  • p-JNK detection LNCaP cells were treated with indicated concentration for 2 hrs, and then stimulated with 25 ug/ml anisomycin for 30 min.
  • Figure 4A shows data on the effects of Enzalutamide and/or JNKi AS602801 (AS) treatment in Luc-LNCaP xenografts.
  • Figure 4B shows tumor growth of Luc-LNCaP xenografts treated with the indicated drugs for 25 days is presented.
  • Fig. 4C shows final tumor weight was obtained from photo of Luc-LNCaP xenograft tumor tissues after mice were sacrificed.
  • Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.
  • Subject refers to any animal, preferably a human patient, livestock, rodent, monkey or domestic pet.
  • Cancer refers any of various cellular diseases with malignant neoplasms characterized by the proliferation of cells. It is not intended that the diseased cells must actually invade surrounding tissue and metastasize to new body sites. Cancer can involve any tissue of the body and have many different forms in each body area. Within the context of certain embodiments, whether “cancer is reduced” may be identified by a variety of diagnostic manners known to one skill in the art including, but not limited to, observation the reduction in size or number of tumor masses or if an increase of apoptosis of cancer cells observed, e.g., if more than a 5 % increase in apoptosis of cancer cells is observed for a sample compound compared to a control without the compound. It may also be identified by a change in relevant biomarker or gene expression profile, such as PSA for prostate cancer, HER2 for breast cancer, or others.
  • A“chemotherapy agent,”“chemotherapeutic,”“anti-cancer agent” or the like refer to molecules that are recognized to aid in the treatment of a cancer.
  • Contemplated examples include the following molecules or derivatives such as temozolomide, carmustine, bevacizumab, procarbazine, lomustine, vincristine, gefitinib, erlotinib, cisplatin, carboplatin, oxaliplatin, 5- fluorouracil, gemcitabine, tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, vinblastine, vindesine, vinorelbine, paclitaxel, taxol, docetaxel, etoposide, ten
  • the terms “prevent” and “preventing” include the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.
  • the terms “treat” and “treating” are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays disease progression.
  • the term "combination with” when used to describe administration with an additional treatment means that the agent may be administered prior to, together with, or after the additional treatment, or a combination thereof.
  • this disclosure relates to methods of treating cancer comprising administering an effective amount of an androgen receptor antagonist in combination with a JNK pathway inhibitor to a subject in need thereof.
  • androgen receptor antagonist is enzalutamide.
  • the JNK pathway inhibitor is bentamapimod.
  • the cancer is prostate cancer.
  • the subject is a human. In certain embodiments, the subject is diagnosed with castration resistant prostate cancer. In certain embodiments, the subject is diagnosed with nonmetastatic castration-resistant prostate cancer. In certain embodiments, the subject is diagnosed with metastatic castration-resistant prostate cancer.
  • Anti-androgens include abiraterone acetate, enzalutamide and apalutamide.
  • Abiraterone inhibits an androgen biosynthesis enzyme expressed in testicular and prostatic tumor tissues.
  • Enzalutamide and apalutamide are androgen receptor inhibitors.
  • this disclosure relates to methods using an androgen receptor antagonist in combination with a JNK pathway inhibitor.
  • the androgen receptor antagonist is enzalutamide, apalutamide, or combinations thereof.
  • this disclosure relates to methods using an inhibitor of an androgen biosynthesis in combination with a JNK pathway inhibitor.
  • the inhibitor of an androgen biosynthesis is abiraterone.
  • this disclosure relates to methods using an i) inhibitor of an androgen biosynthesis and/or an inhibitor of an androgen biosynthesis in combination with ii) a JNK pathway inhibitor and a pharmaceutically acceptable excipient.
  • the inhibitor of an androgen biosynthesis is abiraterone.
  • the androgen receptor antagonist is enzalutamide, apalutamide, or combinations thereof.
  • Anti-androgens include abiraterone acetate, enzalutamide and apalutamide
  • the subject is at risk of, exhibiting symptoms of, or diagnosed with prostate cancer, breast cancer, colorectal cancer, gastric cancer, lung cancer, skin cancer, bladder cancer, brain cancer, kidney cancer, endometrial cancer, pancreatic cancer, and thyroid cancer.
  • contemplated methods include further administering a second anti-cancer agent such as bevacizumab, gefitinib, erlotinib, temozolomide, docetaxel, cis-platin, 5-fluorouracil, gemcitabine, tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, vincristine, vinblastine, vindesine, vinorelbine taxol, taxotere, etoposide, teniposide, amsacrine, topotecan, camptothecin, bortezomib, anagrelide, tamoxifen, toremifene, raloxifene, d
  • the disclosure contemplates treating or preventing prostate cancer using compounds disclosed herein and one more other anti-cancer agents. In certain embodiments, the disclosure contemplates treating or preventing prostate cancer using compounds disclosed herein and leuprolide, goserelin, or buserelin. In certain embodiments, the disclosure contemplates treating or preventing prostate cancer using compounds disclosed herein and flutamide, bicalutamide, enzalutamide, or nilutamide. In certain embodiments, the disclosure contemplates treating or preventing prostate cancer using compounds disclosed herein and ketoconazole or aminoglutethimide.
  • the disclosure contemplates treating or preventing prostate cancer using compounds disclosed herein and abiraterone, bicalutamide, cabazitaxel, bicalutamide, degarelix, denosumab, docetaxel, enzalutamide, cabazitaxel, leuprolide, prednisone, denosumab, sipuleucel-T, or radium 223 dichloride and combinations thereof.
  • the disclosure contemplates treating or preventing breast cancer using compounds disclosed herein and one more other anti-cancer agents. In certain embodiments, the disclosure contemplates treating or preventing breast cancer using compounds disclosed herein and trastuzumab and/or lapatinib. In certain embodiments, the disclosure contemplates treating or preventing breast cancer using compounds disclosed herein and docetaxel and cyclophosphamide. In certain embodiments, the disclosure contemplates treating or preventing breast cancer using compounds disclosed herein and docetaxel, carboplatin, and trastuzumab.
  • the disclosure contemplates treating or preventing breast cancer using compounds disclosed herein and cyclophosphamide, doxorubicin, and 5-fluorouracil (5-FU). In certain embodiments, the disclosure contemplates treating or preventing breast cancer using compounds disclosed herein and docetaxel, doxorubicin, and cyclophosphamide. In certain embodiments, the disclosure contemplates treating or preventing breast cancer using compounds disclosed herein and doxorubicin and cyclophosphamide followed by paclitaxel or docetaxel. In certain embodiments, the disclosure contemplates treating or preventing breast cancer using compounds disclosed herein and 5-FU, epirubicin, and cyclophosphamide followed by docetaxel or paclitaxel.
  • the disclosure contemplates treating or preventing colon cancer using compounds disclosed herein and bevacizumab or cetuximab. In certain embodiments, the disclosure contemplates treating or preventing colon cancer using compounds disclosed herein and 5-FU and leucovorin optionally with bevacizumab. In certain embodiments, the disclosure contemplates treating or preventing colon cancer using compounds disclosed herein and capecitabine optionally with bevacizumab. In certain embodiments, the disclosure contemplates treating or preventing colon cancer using compounds disclosed herein and irinotecan optionally with cetuximab. In certain embodiments, the disclosure contemplates treating or preventing colon cancer using compounds disclosed herein and cetuximab. In certain embodiments, the disclosure contemplates treating or preventing colon cancer using compounds disclosed herein and panitumumab. In certain embodiments, the disclosure contemplates treating or preventing colon cancer using compounds disclosed herein and regorafenib.
  • the disclosure contemplates treating or preventing lung cancer using compounds disclosed herein and a chemotherapy agent is selected from vinorelbine, etoposide, mitomycin C, gemcitabine, irinotecan, pemetrexed, gefitinib, erlotinib, lapatinib, crizotinib, and a vinca alkaloid or combinations thereof.
  • a chemotherapy agent is selected from vinorelbine, etoposide, mitomycin C, gemcitabine, irinotecan, pemetrexed, gefitinib, erlotinib, lapatinib, crizotinib, and a vinca alkaloid or combinations thereof.
  • the vinca alkaloid is vinblastine, vincristine, vindesine, or vinorelbine.
  • the disclosure contemplates treating or preventing lung cancer using compounds disclosed herein and chemotherapy agent is bevacizumab panitumumab, zalutumumab, nimotuzumab, matuzumab, or cetuximab.
  • the disclosure contemplates treating or preventing lung cancer using compounds disclosed herein and a platinum-based agent and/or a taxane e.g., paclitaxel and docetaxel or combinations thereof.
  • the disclosure contemplates treating or preventing brain cancer, glioblastoma multiforme, oligodendroglioma, primitive neuroectodermal tumors, ependymomas, glioma comprising using compounds disclosed herein, e.g., 7- morpholinobenzo[c][l,2,5]oxadiazol-4-amine or optionally substituted derivative or salt thereof to a subject in need thereof.
  • the compounds are optionally administered in combination with temozolomide, procarbazine, carmustine (BCNU), lomustine (CCNU), vincristine, and combinations thereof.
  • procarbazine, lomustine (CCNU) and vincristine are combined.
  • the compounds are optionally administered in combination with irinotecan, cis-platin, carboplatin, methotrexate, etoposide, bleomycin, vinblastine, actinomycin D, cyclophosphamide, or ifosfamide.
  • the disclosure contemplates combinations of compounds disclosed herein with temozolomide.
  • Treatment of glioblastoma includes chemotherapy during and after radiotherapy. On average, chemotherapy after surgery and radiotherapy can initially reduce the tumor size. The use of temozolomide both during radiotherapy and for six months post radiotherapy results in a significant increase in median survival with minimal additional toxicity. This treatment regime is now standard for most cases of glioblastoma where the patient is not enrolled in a clinical trial. Temozolomide seems to work by sensitizing the tumor cells to radiation. The U.S. Food and Drug Administration approved Avastin (bevacizumab) to treat patients with glioblastoma at progression after standard therapy.
  • Avastin bevacizumab
  • the disclosure relates to administering compositions disclosed herein for the management of cancers or tumors in the brain by convection-enhanced delivery (CED).
  • CED is a method of administrating compositions by direct infusion into the brain interstitial spaces utilizing a fluid pressure gradient after catheter placement.
  • the cancer treatments disclosed herein can be applied as a sole therapy or can involve, conventional surgery or radiotherapy or chemotherapy.
  • this disclosure relates to pharmaceutical compositions comprising an androgen receptor antagonist in combination with a INK pathway inhibitor and a pharmaceutically acceptable excipient.
  • the androgen receptor antagonist is enzalutamide.
  • the disclosure relates to pharmaceutical compositions comprising compounds disclosed herein and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is in the form of a pill, capsule, tablet, or saline aqueous buffer.
  • the pharmaceutically acceptable excipient is selected from a saccharide, disaccharide, sucrose, lactose, glucose, mannitol, sorbitol, polysaccharides, starch, cellulose, microcrystalline cellulose, cellulose ether, hydroxypropyl cellulose (HPC), xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), crosslinked sodium carboxymethyl cellulose, dibasic calcium phosphate, calcium carbonate, stearic acid, magnesium stearate, talc, magnesium carbonate, silica, vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, and sodium citrate, methyl paraben, propyl paraben, and combinations thereof.
  • a saccharide disaccharide
  • sucrose lactose
  • glucose
  • compositions disclosed herein may be in the form of pharmaceutically acceptable salts, as generally described below.
  • suitable pharmaceutically acceptable organic and/or inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids known per se (for which reference is made to the references referred to below).
  • the compounds of the disclosure may also form internal salts, and such compounds are within the scope of the disclosure.
  • the compounds of the disclosure contain a hydrogen- donating heteroatom (e.g. NH)
  • the disclosure covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
  • Pharmaceutically acceptable salts of the compounds include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/di
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • suitable salts see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley - VCH, 2002), incorporated herein by reference.
  • a prodrug may include a covalently bonded carrier which releases the active parent drug when administered to a mammalian subject.
  • Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include, for example, compounds wherein a hydroxy group is bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy group.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol functional groups in the compounds.
  • prodrugs form the active metabolite by transformation of the prodrug by hydrolytic enzymes, the hydrolysis of amide, lactams, peptides, carboxylic acid esters, epoxides or the cleavage of esters of inorganic acids. It is well within the ordinary skill of the art to make an ester prodrug, e.g., acetyl ester of a free hydroxy group. It is well known that ester prodrugs are readily degraded in the body to release the corresponding alcohol. See e.g., Imai, Drug Metab Pharmacokinet. (2006) 21(3): 173-85, entitled“Human carboxylesterase isozymes: catalytic properties and rational drug design.”
  • compositions for use in the present disclosure typically comprise an effective amount of compounds and a suitable pharmaceutical acceptable carrier.
  • the preparations may be prepared in a manner known per se, which usually involves mixing the at least one compound according to the disclosure with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions.
  • the compounds may be formulated as a pharmaceutical preparation comprising compounds and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • the pharmaceutical preparations of the disclosure are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
  • unit dosages will contain between 1 and 1000 mg, and usually between 5 and 500 mg, of the compounds of the disclosure, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.
  • the compounds may be administered by a variety of routes including the oral, ocular, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, depending mainly on the specific preparation used.
  • the compounds will generally be administered in an "effective amount", by which is meant any amount of compounds that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which it is administered.
  • such an effective amount will usually be between 0.01 to 1000 mg per kilogram body weight of the patient per day, more often between 0.1 and 500 mg, such as between 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses.
  • the amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated. Reference is made to U.S. Pat. No. 6,372,778, U.S. Pat. No. 6,369,086, U.S. Pat. No. 6,369,087 and U.S. Pat. No. 6,372,733 and the further references mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.
  • the compounds may be mixed with suitable additives, such as excipients, stabilizers or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions.
  • suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, com starch.
  • the preparation may be carried out both as dry and as moist granules.
  • Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil.
  • Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof.
  • Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms.
  • these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
  • compositions When administered by nasal aerosol or inhalation, the compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the disclosure or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents.
  • the formulation may contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.
  • auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.
  • the compounds if desired with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries are brought into solution, suspension, or emulsion.
  • the compounds may also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations.
  • Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, sugar solutions such as glucose or mannitol solutions, or mixtures of the various solvents mentioned.
  • the injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • suitable non-toxic, parenterally-acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • the formulations When rectally administered in the form of suppositories, the formulations may be prepared by mixing the compounds with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • compositions may be extended release formulations.
  • Typical extended release formations utilize an enteric coating.
  • a barrier is applied to oral medication that controls the location in the digestive system where it is absorbed. Enteric coatings prevent release of medication before it reaches the small intestine.
  • Enteric coatings may contain polymers of polysaccharides, such as maltodextrin, xanthan, scleroglucan dextran, starch, alginates, pullulan, hyaluronic acid, chitin, chitosan and the like; other natural polymers, such as proteins (albumin, gelatin etc.), poly-L-lysine; sodium poly(acrylic acid); poly(hydroxyalkylmethacrylates) (for example poly(hydroxyethyl methacrylate)); carboxypolymethylene (for example CarbopolTM); carbomer; polyvinylpyrrolidone; gums, such as guar gum, gum arabic, gum karaya, locust bean gum, tamarind gum, gum tragacanth, agar, pectin, gluten and the like; poly(vinyl alcohol); ethylene vinyl alcohol; polyethylene glycol (PEG); and cellulose ethers, such as hydroxymethylcellulose (HMC), hydroxyethy
  • compositions of the invention in the form of coatings in which the polymer carrier is provided by way of a blend of two or more polymers of, for example, different molecular weights in order to produce a particular required or desired release profile.
  • Microspheres of polylactide, polyglycolide, and their copolymers poly(lactide-co- glycolide) may be used to form sustained-release compounds delivery systems.
  • Compounds may be entrapped in the poly(lactide-co-glycolide) microsphere depot by a number of methods, including formation of a water-in-oil emulsion with water-borne compounds and organic solvent- borne polymer (emulsion method), formation of a solid-in-oil suspension with solid compounds dispersed in a solvent-based polymer solution (suspension method), or by dissolving the compounds in a solvent-based polymer solution (dissolution method).
  • emulsion method formation of a solid-in-oil suspension with solid compounds dispersed in a solvent-based polymer solution
  • dissolution method dissolving the compounds in a solvent-based polymer solution
  • One may attach poly(ethylene glycol) to compounds (PEGylation) to increase the in vivo half-life of circulating
  • Prostate cancer is common cancer in men.
  • ADT androgen deprivation therapy
  • ADT includes surgical castration (orchiectomy), luteinizing hormone-releasing hormone (LHRH) agonists/antagonists, and CYP17 inhibitors, all of which aim to reduce the level of androgens stimulating the growth of prostate cancer cells.
  • LHRH luteinizing hormone-releasing hormone
  • CYP17 inhibitors all of which aim to reduce the level of androgens stimulating the growth of prostate cancer cells.
  • cancer cells continue to grow even when androgen levels are reduced - referred to as castration-resistant prostate cancer (CRPC).
  • CRPC castration-resistant prostate cancer
  • the median overall survival for patients that develop CRPC is reported to be one or two years. (Halabi et al., J Clin Oncol (2014)).
  • Enzalutamide is a drug administered to treat CRPC and works by inhibiting androgen receptors. However, cancer cells can still become resistant to Enzalutamide (ENZ) over time, through a variety of mechanisms (Nakazawa et al., Curr Oncol Rep (2017)). ENZ is may be used to treat prostate cancer that is resistant to other forms of androgen deprivation therapy ADT, but resistance to ENZ can limit its efficacy and lead to (CRPC).
  • JNKi affects cell invasion
  • transwell invasion assays were performed (Fig. 3A and 3B).
  • the JNKi also synergized with ENZ to reduce invasion of LNCaP cells by -80% as compared to DMSO controls (Fig. 3 A), and similar effects were observed in C4-2B cells (Fig. 3B).
  • C4-2B cells are castration resistant, supporting efficacy of this combination in castration resistant patients.
  • western blot analysis of LNCaP cells treated with ENZ and/or JNKi determined that the JNKi AS602801 strongly reduces abundance of AR protein and PSA protein, and this effect is synergistic with co-treatment with ENZ (Fig. 3C).

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Abstract

La présente invention concerne des procédés de traitement ou de prévention du cancer et des compositions pharmaceutiques associées. Dans certains modes de réalisation, la présente invention concerne des procédés de traitement du cancer comprenant l'administration d'une quantité efficace d'une thérapie de privation androgénique en combinaison avec un inhibiteur de la voie JNK à un sujet qui en a besoin. Dans certains modes de réalisation, l'antagoniste du récepteur des androgènes est l'enzalutamide. Dans certains modes de réalisation, l'inhibiteur de la voie JNK est le bentamapimod. Dans certains modes de réalisation, le cancer est le cancer de la prostate.
PCT/US2020/025439 2019-03-29 2020-03-27 Utilisations d'antagonistes du récepteur des androgènes et d'inhibiteurs de la voie jnk et compositions pharmaceutiques associées WO2020205608A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040067953A1 (en) * 2002-03-08 2004-04-08 Stein Bernd M. Combination therapy for treating, preventing or managing proliferative disorders and cancers
US20140018433A1 (en) * 2012-07-13 2014-01-16 Gtx, Inc. Method of treating androgen receptor (ar) -positive breast cancers with selective androgen receptor modulator (sarms)
US20180271849A1 (en) * 2015-09-29 2018-09-27 Kangpu Biopharmaceuticals, Ltd. Pharmaceutical composition and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040067953A1 (en) * 2002-03-08 2004-04-08 Stein Bernd M. Combination therapy for treating, preventing or managing proliferative disorders and cancers
US20140018433A1 (en) * 2012-07-13 2014-01-16 Gtx, Inc. Method of treating androgen receptor (ar) -positive breast cancers with selective androgen receptor modulator (sarms)
US20180271849A1 (en) * 2015-09-29 2018-09-27 Kangpu Biopharmaceuticals, Ltd. Pharmaceutical composition and application thereof

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Title
TAKESHI SATO, SHIBATA WATARU, HIKIBA YOHKO, KANETA YOSHIHIRO, SUZUKI NOBUMI, IHARA SOZABURO, ISHII YASUAKI, SUE SOICHIRO, KAMETA E: "c-Jun N-terminal kinase in pancreatic tumor stroma augments tumor development in mice", CANCER SCIENCE, vol. 108, no. 11, 24 August 2017 (2017-08-24), pages 2156 - 2165, XP055744650, ISSN: 1347-9032, DOI: 10.1111/cas.13382 *

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