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WO2020146845A1 - Compositions et méthodes pour le traitement du cancer de la prostate avec de l'enzalutamide et un inhibiteur de monoamine oxydase a - Google Patents

Compositions et méthodes pour le traitement du cancer de la prostate avec de l'enzalutamide et un inhibiteur de monoamine oxydase a Download PDF

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WO2020146845A1
WO2020146845A1 PCT/US2020/013243 US2020013243W WO2020146845A1 WO 2020146845 A1 WO2020146845 A1 WO 2020146845A1 US 2020013243 W US2020013243 W US 2020013243W WO 2020146845 A1 WO2020146845 A1 WO 2020146845A1
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compound
enz
maoa
arv7
cells
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Chawnshang Chang
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University of Rochester
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University of Rochester
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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention generally relates to novel therapeutic methods and pharmaceutical compositions for treating cancer. More particularly, the invention relates to a novel approach to addressing drug resistance in prostate cancer treatment.
  • PCa Prostate cancer
  • ADT androgen deprivation therapy
  • the invention is based in part on the unexpected discovery that inhibitors of MAO A can be used to prevent, delay, reduce and/or reverse EnzR resistance and to increase, restore and/or prolong the effective treatment of prostate cancer with anti-androgen compounds, such as Enz.
  • MO AO inhibitors can delay the onset and development and/or reduce the magnitude of EnzR and suppress EnzR tumors.
  • MAOA is highly expressed in various Enz resistant PCa cells.
  • Targeting MAOA with its specific inhibitors, for example clorgyline or phenelzine, both FDA-proved for treating Parkinson and depression, can lead to re-sensitized Enz-R cells in response to Enz treatment to further suppress Enz-R cell growth.
  • This result indicates that certain currently FDA-proved drugs may be immediately developed and used as new therapy to overcome the Enz-induced castration resistance.
  • the invention generally relates to a pharmaceutical composition, which includes: a first compound of Formula (I)
  • each of the first and second compounds is present in an amount such that the pharmaceutical composition is effective in the treatment of prostate cancer, or a related disease or condition thereof, in a mammal, including a human, and a pharmaceutically acceptable carrier.
  • the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.
  • the invention generally relates to a method for treating castration resistant prostate cancer, or a related disease or condition thereof.
  • the method includes administering to a subject in need thereof a pharmaceutical composition disclosed herein.
  • the invention generally relates to a method for treating castration resistant prostate cancer, or a related disease or condition thereof.
  • the method includes administering to a subject in need thereof a first compound of Formula (I)
  • the invention generally relates to a method for treating castration resistant prostate cancer, or a related disease or condition thereof.
  • the method includes: administering to a subject in need thereof a first compound of Formula (I)
  • a pharmaceutically acceptable salt, ester or pro-drug thereof in an amount effective in the treatment of castration resistant prostate cancer or a related disease or condition thereof in a mammal, including a human; monitoring the subject to detect a development of drug resistance to the first compound; upon the subject being detected of the development of drug resistance to the first compound, administering to the subject a second compound which is an inhibitor of monoamine oxidase A, in an amount effect to reduce or eliminate drug resistance to the first compound; and monitoring the subject to detect a level of drug resistance to the first compound.
  • the invention generally relates to a method for treating a drug resistance in connection with a cancer treatment.
  • the method includes: administering to a subject in need thereof a second compound which is an inhibitor of monoamine oxidase A, in an amount effective to prevent, delay, reduce or reverse resistance to a treatment of prostate cancer, or a related disease or condition thereof in a mammal, including a human.
  • C The qPCR and Western blot analysis of MAOA levels in EnzRl- C4-2 and EnzSl-C4-2 cells.
  • E MAOA and ARv7 mRNA levels by qPCR following treatment with DMSO or 10 mM Enz in EnzSl-C4-2 cells for 6 days.
  • F MAOA activity analyzed in EnzSl-C4-2 cells treated with 10 mM Enz for 6 days.
  • G Absolute copy numbers of MAOA mRNA normalized to copy number of RPL13A in CTCs isolations from 288 patients. Those samples were grouped by CTC and ARv7 status: CTC-, CTC+/ARv7-, and CTC+/ARv7+.
  • FIG. 2. Targeting MAOA re-sensitizes EnzR cells to Enz and suppresses EnzR cell growth.
  • E-G EnzRl-C4-2, EnzR2-C4-2, EnzR3-22Rvl cells, respectively, were treated w/o 10 mM Enz and 5 mM phenelzine, and cell viability was analyzed.
  • H-J The EnzRl-C4-2, EnzR2-C4-2, EnzR3-22Rvl cells with pLKO or shMAOA cells were treated w/o Enz and cell viability was analyzed.
  • K MAO A was overexpressed (oeMAOA) in EnzSl-C4-2 cells and then the cells treated w/o Enz and cell viability was analyzed.
  • (L) EnzSl-C4-2 cells were treated w/o 10 mM Enz and cell viability was analyzed.
  • (M) EnzSl-C4-2 cells were first treated (w/o) 10 mM Enz for 1.5 month. And then the cells were seeding and the cell viability under 10 mM Enz treatment was analyzed by MTT assay.
  • (N-O) EnzSl-C4-2 cells were treated w/o 10 mM Enz and 1 mM,2.5mM clorgyline (clg) for 1.5 month. And then the cell viability under 10 mM Enz treatment was analyzed. Quantitation is mean ⁇ SEM, P-value was determined by two-tailed paired t test. P-values are, * ⁇ 0.05, ** ⁇ 0.005.
  • FIG. 3 Mechanism dissection of how Enz increases the MAOA expression: via increasing ARv7.
  • A-B PC3 cells were treated with/without (w/o) 10 mM Enz and 5 mM clorgyline or 10mM clorgyline. (The cell viability was analyzed by MTT assay.
  • C EnzSl-C4-2 cells were treated with 10 mM Enz for different time points. The ARv7 and MAOA mRNA level were analyzed by qPCR (left) and western blot (right).
  • D The mRNA levels of ARv7 and MAOA were analyzed in EnzRl-C4-2 PWPI and PWPI-ARv7 cells.
  • FIG. 4. Enz up-regulates the MAOA transactivation in transcriptional level and protein level.
  • A Schematic depiction of putative ARE on MAOA promoter region. The mutant ARE was marked by italic font.
  • B ChIP assay was performed to identify that endogenous AR and Flag-ARv7 bind to the putative ARE on MAO A promoter in EnzRl-C4-2 and EnzSl -pWPI- flag-ARV7 cells.
  • EnzRl cells were infected by Flag-ARv7 or Flag-ARfl virus. The ChIP assay were performed to analyze Flag-AR and Flag-ARv7 binding on MAOA promoter region in EnzRl cells.
  • FIG. 5 MAOA activates Hypoxia signaling to promote the Enzalutamide- resistance.
  • A The mRNA levels of Glutl, N-Cadherin, Timp and VEGF-A in EnzSl-C4-2 and EnzRl -C4-2 cells were analyzed by qPCR.
  • B In EnzRl -C4-2 cells, MAOA was knocked down by shRNA. And the mRNA levels of MAOA, Slug, VEGF-A and HIF-Ia were analyzed by qPCR (left), as well asHIF-Ia and VEGF-A expression by western blot (right).
  • (C) EnzRl -C4-2 cells were treated with/without 5mM clorgyline, and the mRNA and protein level of MAOA, HIF-Ia and VEGF-A were analyzed by qPCR (left) and western blot (right).
  • A The in vivo PDX-PCa mouse model data revealed that injection with Enz (30mg/kg/every other day) increased the MAOA, ARv7 and p-p38 level.
  • B, C Mice implanted with EnzR3-22Rvl xenografts were treated with vehicle control, Enz (30 mg/kg), clorgyline (10 mg/kg), phenelzine (30 mg/kg), Enz+cl orgyline (30 mg/kg+10 mg/kg), or Enz+phenelzine (30 mg/kg+30 mg/kg).
  • B Western blot analysis of MAO-A expression in EnzS4_C4-2B parental and Enz-R4_C4-2B EnzR cells.
  • C VCaP cells were treated by Enz for 10 days and then the ARv7 and MAO-A protein levels were examined by WB. For A Quantitations are mean ⁇ SEM, P-value was determined by two-tailed paired t test. P values are ** ⁇ 0.005, *** ⁇ 0.001.
  • FIG. 9. MGEA11 and HSD3B1 expression EnzR and EnzS cells were analyzed by qPCR.
  • B The EnzRl cells were treated w/o lOuM clorgyline for 24 hours. The MAO-A and ARv7 expression were analyzed by WB.
  • FIG. 10. The ARfl and ARv7 binding on MAO-A promoter regions in presence of DHT (A) or in the absence of DHT (Etoh) (B) were analyzed based on ChIP-seq data (GEO: GSE106559).
  • C The quantification of ARfl and ARv7 binding on the MAO-A promoter region.
  • FIG. 11 (A) Western blot analysis to identify the knocking efficiency of MAO-A in EnzRl_C4-2 and EnzR2 cells. (B) The qPCR analysis (left) to identify the mRNA level and Western blot analysis (right) of HIF-Ia and VEGF-A in EnzRl_C4-2 pLVTHM and shHIFla cells. For B Quantitations are mean ⁇ SEM, P-value was determined by two-tailed paired t test. P values are ** ⁇ 0.005, *** ⁇ 0.001.
  • FIG. 12 Mice implanted with EnzR3-22RVl-luc xenografts were treated with vehicle control, Enz (30 mg/kg), cl orgyline (10 mg/kg), phenelzine (30 mg/kg), Enz+cl orgyline (30 mg/kg+10 mg/kg), or Enz+phenelzine (30 mg/kg+30 mg/kg). The tumor sizes were monitored by In vivo imaging system (IVIS).
  • B-C After sacrifice, tumors of the 6 groups were collected (B) and weighed (C).
  • D IHC staining of Ki-67 and VEGF-A in EnzR3-22Rvl-luc tumors were performed. For D Quantitations are mean ⁇ SEM, P-value was determined by two- tailed paired t test. P values are ** ⁇ 0.005.
  • FIG. 13 Exemplary primer and plasmid sequences.
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and trans- isomers, R- and ⁇ -enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90: 10, 95:5, 96:4, 97:3, 98:2, 99: 1, or 100:0 isomer ratios are contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.
  • Enzalutamide ( ak.a ., MDV3100 and Xtandi, CAS No. 915087-33-1) is a synthetic, non-steroidal pure antiandrogen that was developed for the treatment of metastatic castration- resistant prostate cancer.
  • the IUPAC name of the compound is 4-(3-(4-Cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide.
  • the structure of Enzalutamide is depicted by formula (I).
  • the term“effective amount” of an active agent refers to an amount sufficient to elicit the desired biological response.
  • the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the patient.
  • treatment refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred.
  • Treatment may be directed at one or more effects or symptoms of a disease and/or the underlying pathology.
  • the treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease.
  • reduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.
  • the terms“prevent”,“preventing”, or“prevention” refer to a method for precluding, delaying, averting, or stopping the onset, incidence, severity, or recurrence of a disease or condition.
  • a method is considered to be a prevention if there is a reduction or delay in onset, incidence, severity, or recurrence of a disease or condition or one or more symptoms thereof in a subject susceptible to the disease or condition as compared to a subject not receiving the method.
  • the disclosed method is also considered to be a prevention if there is a reduction or delay in onset, incidence, severity, or recurrence of osteoporosis or one or more symptoms of a disease or condition in a subject susceptible to the disease or condition after receiving the method as compared to the subject's progression prior to receiving treatment.
  • the reduction or delay in onset, incidence, severity, or recurrence of osteoporosis can be about a 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between.
  • the term“pharmaceutically acceptable” excipient, carrier, or diluent refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ring
  • wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • the terms“isolated” or“purified” refer to a material that is substantially or essentially free from components that normally accompany it in its native state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography.
  • the term“subject” refers to any animal (e.g ., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment.
  • the terms“subject” and“patient” are used interchangeably herein in reference to a human subject.
  • the term“low dosage” refers to at least 5% less (e.g., at least 10%, 20%, 50%, 80%, 90%, or even 95%) than the lowest standard recommended dosage of a particular compound formulated for a given route of administration for treatment of any human disease or condition.
  • a low dosage of an agent that is formulated for administration by inhalation will differ from a low dosage of the same agent formulated for oral administration.
  • the term“high dosage” is meant at least 5% (e.g., at least 10%, 20%, 50%, 100%, 200%, or even 300%) more than the highest standard recommended dosage of a particular compound for treatment of any human disease or condition.
  • prodrug refers to a pharmacological derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug.
  • prodrugs are pharmaceutically active in vivo, when they undergo solvolysis under physiological conditions or undergo enzymatic degradation.
  • Prodrug compounds herein may be called single, double, triple, etc., depending on the number of biotransformation steps required to release the active drug within the organism, and the number of functionalities present in a precursor-type form.
  • Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism. (See, Bundgard, Design of Prodrugs, pp. 7-9,21-24,
  • Prodrugs commonly known in the art include well-known acid derivatives, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, amides prepared by reaction of the parent acid compound with an amine, basic groups reacted to form an acylated base derivative, etc.
  • acid derivatives such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, amides prepared by reaction of the parent acid compound with an amine, basic groups reacted to form an acylated base derivative, etc.
  • other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability.
  • those of skill in the art will appreciate that certain of the presently disclosed compounds having free amino, arnido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g ., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of the presently disclosed compounds.
  • the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma- aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.
  • Prodrugs also include compounds having a carbonate, carbamate, amide or alkyl ester moiety covalently bonded to any of the above substiruents disclosed herein.
  • Isotopically-labeled compounds are also within the scope of the present disclosure.
  • an “isotopically-labeled compound” refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • the compounds may be useful in drug and/or substrate tissue distribution assays. Tritiated ( 3 H) and carbon-14 ( 14 C) labeled compounds are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium ( 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds presently disclosed, including pharmaceutical salts, esters, and prodrugs thereof, can be prepared by any means known in the art.
  • substitution of normally abundant hydrogen (3 ⁇ 4) with heavier isotopes such as deuterium can afford certain therapeutic advantages, e.g., resulting from improved absorption, distribution, metabolism and/or excretion (ADME) properties, creating drugs with improved efficacy, safety, and/or tolerability. Benefits may also be obtained from replacement of normally abundant 12 C with 13 C. (See, WO 2007/005643, WO 2007/005644, WO 2007/016361, and WO 2007/016431.)
  • Stereoisomers e.g ., cis and trans isomers
  • optical isomers of a presently disclosed compound e.g., R and S enantiomers
  • racemic, diastereomeric and other mixtures of such isomers are within the scope of the present disclosure.
  • Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% (“substantially pure”), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.
  • Solvates and polymorphs of the compounds of the invention are also contemplated herein.
  • Solvates of the compounds of the present invention include, for example, hydrates.
  • Any appropriate route of administration can be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intraventricular, intracorporeal, intraperitoneal, rectal, or oral administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the compounds described herein or derivatives thereof are admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate
  • solution retarders as for example, paraffin
  • absorption accelerators as for example,
  • the dosage forms may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others known in the art.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, such as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3- butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • the composition can also benzoate, propyleneglycol, 1,3- butylenegly
  • the invention provides a unique approach to treatment of prostate cancer, particularly drug resistance prostate cancer.
  • the novel therapeutic methods and compositions provided herein can benefit prostate cancer patients in terms of increased survival rate and improved treatment outcome.
  • Methods and compositions of the invention can be used to prevent, delay, reduce and/or reverse drug resistance and to increase, restore and/or prolong the effective treatment of prostate cancer with anti-androgen compounds.
  • Enzalutamide an anti-androgen agent
  • the current standard therapy to further suppress CRPC involves either docetaxel (Doc)- chemotherapy or ADT with either using Enz to prevent androgens binding to AR. or using abiraterone (ABI) to further suppress the androgen synthesis in renal.
  • Doc docetaxel
  • ADT abiraterone
  • Enz resistance after an average of 4.8 months response to Enz. (Scher, et al. 2012 N Engl J Med 367 , 1187-1197; Dhingra, et al. 2013 Mini Rev Med Chem 13, 1475-1486.)
  • EnzR The mechanism by which CRPC patients received Enz develop EnzR remains not fully understood. Certain studies indicated the possible involvement of multiple mechanisms. For instance, Enz or its derivative ARN-509 ( a.k.a ., JNJ-56021927) may induce an AR. point mutation at AR.876 (a missense mutation of phenylalanine 876 to leucine in the Ligand-Binding- Domain (LBD) of AR, named AR-F876L) that is no longer sensitive to Enz treatment. (Korpal, et al. 2013 Cancer Discovery 3, 1030-1043; Joseph et al. 2013 Cancer Discovery 3, 1020-1029.)
  • LBD Ligand-Binding- Domain
  • GR glucocorticoid receptor
  • MAOA is a key enzyme in catalyzing the deamination of amines, and play key roles in inducing some neurotransmitters including norepinephrine, dopamine and serotonin.
  • inhibitors of MO AO such as clorgyline or phenelzine
  • MO AO can be used to effectively prevent, delay, reduce and/or reverse EnzR resistance and to increase, restore and/or prolong the effective treatment of prostate cancer with anti-androgen compounds, such as Enzalutamide and its derivative ARN-
  • Clorgyline is a selective and irreversible inhibitor of MAOA.
  • Phenelzine is a non- selective and irreversible MAOA inhibitor of the hydrazine class. Phenelzine is approved and used as an antidepressant and anxiolytic.
  • Potential side effects of treatment with MAOA inhibitors such as phenelzine include dizziness, drowsiness, tiredness, weakness, problems sleeping, constipation, and dry mouth.
  • EnzR the potential benefit of MAOA inhibitors in restoration of Enz sensitivity would in many cases outweigh the risk of such side effects.
  • dosage adjustment may offer patient therapeutic benefit with manageable risk exposure.
  • the present invention enables a novel and ready therapy to suppress the Enz- resistant CRPC progression and to extend survival of CRPC patients.
  • a combination of a MO AO inhibitor and Enz may be used at the beginning of therapy.
  • sequential treatment with Enz therapy at the beginning may be followed by addition of a MO AO inhibitor at or after confirmation of EnzR ( e.g ., when decreased PSA start to rise again).
  • the invention generally relates to a pharmaceutical composition, which includes: a first compound of Formula (I)
  • the pharmaceutical composition is effective in the treatment of prostate cancer, or a related disease or condition thereof, in a mammal, including a human, and a pharmaceutically acceptable carrier.
  • each of the first and second compounds is present in an amount such that the pharmaceutical composition is effective in delaying the onset of or delaying the development of drug resistance. In certain embodiments, each of the first and second compounds is present in an amount such that the pharmaceutical composition is effective in delaying the onset of drug resistance. In certain embodiments, each of the first and second compounds is present in an amount such that the pharmaceutical composition is effective in delaying the development of drug resistance.
  • each of the first and second compounds is present in an amount such that the pharmaceutical composition is effective in reducing or reversing drug resistance. In certain embodiments, each of the first and second compounds is present in an amount such that the pharmaceutical composition is effective in reducing drug resistance. In certain embodiments, each of the first and second compounds is present in an amount such that the pharmaceutical composition is effective in reversing drug resistance.
  • the first and second compounds may be present in the pharmaceutical composition at any suitable ratios.
  • the weight ratio of the first compound to the second compound is from about 10 : 1 to about 1 : 10 (e.g., from about 7 : 1 to about 1 : 7, from about 5 : 1 to about 1 : 5, from about 3 : 1 to about 1 : 3, from about 2 : 1 to about 1 : 2, about 1 : 1).
  • the first compound may be present in the pharmaceutical composition in any suitable amount, for example in a unit dosage of, in the range of about 0.1 mg to about 1,000 mg, about 1 mg to about 500 mg, about 1 mg to about 10 mg, about 10 mg to about 250 mg, about 10 mg to about 125 mg, about 10 mg to about 100 mg, about 10 mg to about 75 mg, about 10 mg to about 50 mg, about 10 mg to about 25 mg.
  • the second compound may be present in the pharmaceutical composition in any suitable amount, for example in a unit dosage of, in the range of about 0.1 mg to about 1,000 mg, about 1 mg to about 500 mg, about 1 mg to about 10 mg, about 10 mg to about 250 mg, about 10 mg to about 125 mg, about 10 mg to about 100 mg, about 10 mg to about 75 mg, about 10 mg to about 50 mg, about 10 mg to about 25 mg.
  • the pharmaceutical composition is suitable for oral administration.
  • the pharmaceutical composition is suitable for intravenous, intramuscular, or subcutaneous administration.
  • any suitable inhibitor(s) of monoamine oxidase may be used in preparing the pharmaceutical composition of the invention.
  • the pharmaceutical composition includes a single inhibitor of monoamine oxidase (e.g ., MAOA).
  • the pharmaceutical composition includes two or more inhibitors of monoamine oxidase (e.g., MAOA) in a combination.
  • Exemplary inhibitors of MAOA include cl orgyline and phenelzine.
  • the second compound is clorgyline.
  • the weight ratio of the first compound to clorgyline is from about 7 : 1 to about 1 : 7, from about 5 : 1 to about 1 : 5, from about 3 : 1 to about 1 : 3, from about 2 : 1 to about 1 : 2, about 1 : 1
  • the second compound is phenelzine. In certain embodiments,
  • the weight ratio of the first compound to phenelzine is from about 7 : 1 to about 1 : 7, from about 5 : 1 to about 1 : 5, from about 3 : 1 to about 1 : 3, from about 2 : 1 to about 1 : 2, about 1 : 1.
  • the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.
  • the unit dosage form is in the form of a tablet or capsule suitable for oral administration.
  • the unit dosage form is in the form of a liquid solution or suspension suitable for intravenous, intramuscular, or subcutaneous administration.
  • the invention generally relates to a method for treating prostate cancer, or a related disease or condition thereof.
  • the method includes administering to a subject in need thereof a pharmaceutical composition disclosed herein.
  • the method further include: administering to the subject one or more other anti-cancer agents.
  • the one or more other anti-cancer agents may be any suitable agent, for example, a chemotherapeutic agent.
  • chemotherapeutic agents include Erlotinib (TARCEVA®, Genentech/OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787/ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU (5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib
  • alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB
  • calicheamicin especially calicheamicin gammall and calicheamicin omegall (Angew Chem. Inti. Ed. Engl. (1994) 33: 183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis,
  • dactinomycin dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, ADRIAMYCIN ® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esonibicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, p
  • demecolcine diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin;
  • novantrone novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA ® );
  • ibandronate CPT-11 ; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.
  • DMFO difluoromethylomithine
  • the invention generally relates to a method for treating castration resistant prostate cancer, or a related disease or condition thereof.
  • the method includes administering to a subject in need thereof a first compound of Formula (I)
  • the second compound is administered simultaneously with the first compound, or subsequently after the administration of the first compound.
  • the subject has been detected of the development of drug resistance to the first compound and the method is applied.
  • the subject has not been detected of the development of drug resistance to the first compound and the method is applied.
  • the drug resistance results from or is related to Arv7 and/or AR mutant.
  • the first and/or the second compound is administered orally.
  • the first and/or the second compound is administered intravenously, intramuscularly, or subcutaneously.
  • the second compound is clorgyline.
  • the second compound is phenelzine.
  • the method further includes administering to the subject one or more other anti-cancer agents (e.g., a chemotherapeutic agent).
  • one or more other anti-cancer agents e.g., a chemotherapeutic agent.
  • the invention generally relates to a method for treating prostate cancer, or a related disease or condition thereof.
  • the method includes: administering to a subject in need thereof a first compound of Formula (I)
  • a pharmaceutically acceptable salt, ester or pro-drug thereof in an amount effective in the treatment of prostate cancer or a related disease or condition thereof in a mammal, including a human; monitoring the subject to detect a development of drug resistance to the first compound; upon the subject being detected of the development of drug resistance to the first compound, administering to the subject a second compound which is an inhibitor of monoamine oxidase A, in an amount effect to reduce or eliminate drug resistance to the first compound; and monitoring the subject to detect a level of drug resistance to the first compound.
  • the method further includes: upon the subject being detected of the development of drug resistance to the first compound, continuing to administer the subject the first compound.
  • the method further includes: upon the subject being detected of the development of drug resistance to the first compound, halting the administration of the first compound, and upon the subject being detected of a substantial reduction or disappearance of drug resistance, re-starting the administration of the first compound.
  • the drug resistance results from or is related to Arv7 and/or AR mutant.
  • the first and/or the second compound is administered orally.
  • the first and/or the second compound is administered intravenously, intramuscularly, or subcutaneously.
  • the second compound is clorgyline.
  • the second compound is phenelzine.
  • the method further includes administering to the subject one or more other anti-cancer agents (e.g ., a chemotherapeutic agent).
  • the invention generally relates to a method for treating a drug resistance in connection with a cancer treatment. The method includes: administering to a subject in need thereof a second compound which is an inhibitor of monoamine oxidase A, in an amount effective to prevent, delay, reduce or reverse resistance to a treatment of prostate cancer, or a related disease or condition thereof in a mammal, including a human.
  • the method is effective in delaying the onset of or delaying the development of drug resistance.
  • the method is effective in reducing or reversing drug resistance.
  • the resistance is to a compound having Formula (I)
  • results disclosed herein showed that targeting MAOA with anti-depression phenelzine or clorgyline can restore Enz-sensitivity to further suppress EnzR cell growth via altering the Enz/ARv7/MAOA signaling.
  • EnzRl-C4-2 CRPC C4-2 cells generated after chronic culture of CRPC C4-2 cells in media containing increasing Enz concentrations from 10 to 30 mM for 1 year
  • EnzR2-C4-2 we also used the naturally Enz-resistant cell line, CWR22Rvl, and named them as EnzR3-CWR22Rvl.
  • EnzR C4-2B cells from Dr. Allen Gao and named as EnzR4-C4-2B in these studies.
  • an increase in MAOA expression in Enz-treated cells may also play a role in mediating the Enz- resistance.
  • Subseqeunt analysis focused on patients treated with Enz with paired samples collected at treatment baseline and at disease progression.
  • CTCs that remained
  • Clorgyline or Phenelzine the selective inhibitor of MAOA, can restore Enz-sensitivity to further suppress EnzR cell growth
  • EnzRl-C4-2 cell proliferation was also suppressed by adding Clorgyline to Enz treatment (49% suppression), suggesting restoration of Enz sensitivity (FIG. 2B). Similar results were obtained in EnzR2-C4-2 cells (56% suppression) (FIG. 2C) or EnzR3-CWR22RVl(43% suppression) cells (FIG. 2D).
  • OE-ARv7 can decrease the Enz sensitivity, however, knockdown MAOA can reverse the ARv7 effects on Enz sensitivity, suggesting that ARv7 decrease Enz sensitivity dependent on MAOA.
  • Results from luciferase assay via constructing the 3Kb MAOA promoter containing this ARE (or mutant ARE) into PGL3 reporter plasmid also confirmed that treating with Enz to increase ARv7 expression or direct adding ARv7-cDNA (OE-ARv7) could increase the MAOA expression at the transcriptional level with wild-type ARE in both EnzSl-C4-2 and PC3 cells (FIG. 4D-E), and not with mutant ARE (see sequences in FIG. 4 A) in the PC3 cells (FIG. 4F).
  • Enz- increased ARv7 can lead to increase the MAOA expression via protein stability.
  • CHX protein synthesis inhibitor cycloheximide
  • EnzRl-C4-2 cells Suppressing HIF-Ia with HIF-1 -shRNA also reduced its target gene
  • FIG. 6A xenografted PDX tumors
  • mice were treated in groups as follows, 1) vehicle, 2) Enz(10mg/kg), 3) clorgyline (lOmg/kg), 4) phenelzine(30mg/kg), 5) Enz + clorgyline, and 6) Enz + phenelzine, and i.p. injected every two days for 4 weeks.
  • EnzR3-22RV14uc cells we used in vivo imaging system (IVIS) to monitor the tumor sizes weekly. After 4 weeks injections, we sacrificed the mice (4 mice/group in the l st -set and 10 mice/group in the 2 nd -set) 2 days after the final treatment, and then measured the tumor weights.
  • EnzR3-22Rvl4uc (FIG. 12A-B) growth.
  • Enz (lOmg/kg every two days for 4 weeks) with Clorgyline (lOmg/kg every two days for 4 weeks) or Phenelzine
  • EnzR3-22Rvl4uc (FIG. 12A-B) tumors growth. Tumor volumes and weight after sacrifice also confirmed that combining Enz and Clorgyline or Phenelzine can suppress EnzR3-22Rvl and EnzR3-22Rvl4uc tumors progression in mice compared with Enz alone and control vehicle group (FIG. 6C & FIG. 12C)
  • Phenelzine can overcome Enz-resi stance to further suppress the growth of EnzR tumors in the well-established EnzR in vivo models.
  • CWR-22RV1, VCaP and PC-3 cell lines were purchased from the American Type Culture Collection (ATCC, Manassas, VA) and cultured in RPMI 1640 with 10% FBS.
  • HEK293T cells were purchased from the American Type Culture Collection (ATCC, Manassas, VA) and cultured in DMEM with 10% FBS.
  • ATCC American Type Culture Collection
  • DMEM fetal bovine serum
  • the EnzSl-C4-2 cell line was a gift from Dr.
  • EnzS4-C4-2B and EnzR4-C4-2B cell lines were gifts from Dr Allen Gao from UC Davis.
  • C4-2 EnzR cell lines were generated via chronic culture of CRPC C4-2 cells in media containing increasing Enz (from 10 mM to 30 mM), with the increased concentration added when cells were no longer sensitive (EnzRl_C4-2) or continuous culture with 10 mM Enz for 6 months (EnzR2_C4-2).
  • the sh-ARv7 was constructed into the pLKO.1 lentiviral vector as reported previously.
  • RNAs were isolated using Trizol reagent (Invitrogen, Grand Island, NY). One pg of total RNA was subjected to reverse transcription using Superscript III transcriptase (Invitrogen). RT-PCR was conducted using a Bio-Rad CFX96 system with SYBR green to determine the mRNA expression level of a gene of interest. Expression levels were normalized to GAPDH level.
  • EnzS_C4-2 and EnzRl_C4-2 cells were prepared for RNA-seq.
  • mRNA was first isolated from total RNA treated with DNase I using Magnetic Oligo (dT) Beads and was fragmented. Then, the double-stranded cDNA was synthesized with random hexamer primers and was further subjected to end-repair and adapter ligation using T4 DNA ligase. The products of ligation reaction were purified on 2% agarose gel and cDNA fragments (about 200 bp) were recovered. PCR was carried out to enrich the purified cDNA template. Finally, the cDNA library was constructed. After validating on Quit and Bioanalyzer, the library was sequenced using Illumina HiSeq 2500 according to the manufacturer's instruction. Western blot analysis
  • Cells were lysed in RIPA buffer and proteins (20-40 pg) were separated on 8-10% SDS/PAGE gel and then transferred onto PVDF membranes (Millipore, Billerica, MA). After blocking membranes, they were incubated with primary antibodies, then HRP-conjugated secondary antibodies, and visualized using ECL system (Thermo Fisher Scientific, Rochester, NY).
  • the MAOA, GAPDH, tubulin, VEGF-A, Ki67and HIF-1 antibodies were from Santa Cruz Biotechnology, Inc (Santa Cruz).
  • the ARv7 antibody was purchased from Precision Antibody (Columbia, MD).
  • P-P38 antibody was purchased from Cell signaling Technology (Danvers, MA).
  • MAO-Glo assay systems were purchased from Promega (Madison, WI). The cells were lysed by luciferase lysis buffer, and the cell lysates were applied to analyze the MAOA activity by the MAO-Glo kit.
  • ChIP Chromatin Immunoprecipitation Assay
  • PC3-Pwpi and PC3-oeARv7 cells were plated in 24-well plates and co-transfected with PGL3-MAOA-promotercontaining the WT-ARE or mutant ARE and pRL-TK, which is used as internal control using Lipofectamine (Invitrogen). After 48hrs transfection, . Luciferase activity was measured by Dual-Luciferase Assay (Promega, Madison, WI) according to the manufacturer’s manual. The EnzSl cells were transfected with PGL3-MAOA-promoter containing the WT-ARE and pRL-TK using Lipofectamine. After 12 hrs of transfection, the cells were treated with lOuM Enz for 1, 2 and 4 days and then the luciferase activity was measured.
  • PCa-133 PDX samples are the gifts from Dr. Sankar N. Maity from MD
  • EnzR3-22Rvl, EnzR3-22Rvl-luc and EnzRl-C4-2 were mixed with Matrigel (1 : 1) and injected into the prostates of 6- to 7-week old male nude mice (EnzR3-22Rvl-luc and EnzR3-22Rvl) or B-NDG mice (EnzRl-C4-2). Tumor-bearing mice were randomized into four groups and treated by i.p.
  • EnzR3-22Rvl-luc tumors IVIS was used weekly to monitor tumor growth. We imaged the mice a final time 2 days after the final treatment, sacrificed the mice, and monitored tumor growth with the IVIS (EnzR3-22Rvl-luc) as well as tumor sizes and tumor weights.
  • CTC circulating tumor cells
  • CTC samples used for MAOA expression analysis were excess“left-over” cDNA samples from an ongoing prospective blood-based CTC ARv7 study in men with metastatic CRPC.
  • Patient enrollment, blood collection, processing, CTC isolation, cDNA prepartion, and ARv7 detection procedures were described previosuly (Antonarakis ES, Lu C, Luber B, et al. Clinical Significance of Androgen Receptor Splice Variant-7 mRNA Detection in Circulating Tumor Cells of Men With Metastatic Castration-Resistant Prostate Cancer Treated With First- and Second-Line Abiraterone and Enzalutamide. This study was approved by the Johns Hopkins University institutional review board, and patients provided written informed consent.
  • Primer sequences used for MAOA were 5'- AATTCAGCGGCTTCCAATGG-3'(forward) and 5'-CAAGTCGATCAGCTTTCCGG- 3'(reverse); Primer sequences used for RPL13A were 5'- CCTGGAGGAGAAGAGGAAAGAGA-3 ' (forward) and 5'-
  • TTGAGGACCTCTGTGTATTTGTCAA-3' (reverse) resistance Patient treatment status and sample collection timepoints were unblinded after laboratory data was generated.
  • 90 were CTC negative (CTC-)
  • 127 were CTC positive (CTC+) but ARv7 negative (ARv7-)
  • 71 were CTC+ and ARv7 positive (ARv7+).
  • MAOA expression data was normalized to the control gene (RPL13A), and normalized data presnted for each biomaker group according to CTC and ARv7 status, as well as each pre- and post-treatment pairs.

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Abstract

L'invention concerne de nouvelles méthodes thérapeutiques et des compositions pharmaceutiques pour le traitement du cancer de la prostate avec un taux de survie accru et un résultat de traitement amélioré. Les méthodes et compositions de l'invention peuvent être utilisées pour prévenir, retarder et/ou réduire la résistance aux médicaments et pour augmenter, restaurer et/ou prolonger le traitement efficace du cancer de la prostate avec des composés anti-androgènes.
PCT/US2020/013243 2019-01-11 2020-01-11 Compositions et méthodes pour le traitement du cancer de la prostate avec de l'enzalutamide et un inhibiteur de monoamine oxydase a Ceased WO2020146845A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007005644A2 (fr) 2005-07-01 2007-01-11 Concert Pharmaceuticals Inc. Nouvelles aryloxypropanamines
WO2007005643A2 (fr) 2005-07-01 2007-01-11 Concert Pharmaceuticals Inc. Nouveaux aryloxyphenylpropanamines
WO2007016431A2 (fr) 2005-07-29 2007-02-08 Concert Pharmaceuticals Inc. Nouveaux derives de benzo[d][1,3]-dioxol
WO2007016361A2 (fr) 2005-07-29 2007-02-08 Concert Pharmaceuticals Inc. Nouveaux composes pharmaceutiques
WO2013016580A2 (fr) * 2011-07-26 2013-01-31 University Of Southern California Inhibiteurs de monoamine oxydase et procédés pour le traitement et le diagnostic du cancer de la prostate
US20180055915A1 (en) * 2016-03-11 2018-03-01 University Of Rochester Compositions and methods for treating prostate cancer
US20180177786A1 (en) * 2011-07-26 2018-06-28 University Of Southern California Monoamine oxidase inhibitors and methods for treatment and diagnosis of prostate cancer

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007005644A2 (fr) 2005-07-01 2007-01-11 Concert Pharmaceuticals Inc. Nouvelles aryloxypropanamines
WO2007005643A2 (fr) 2005-07-01 2007-01-11 Concert Pharmaceuticals Inc. Nouveaux aryloxyphenylpropanamines
WO2007016431A2 (fr) 2005-07-29 2007-02-08 Concert Pharmaceuticals Inc. Nouveaux derives de benzo[d][1,3]-dioxol
WO2007016361A2 (fr) 2005-07-29 2007-02-08 Concert Pharmaceuticals Inc. Nouveaux composes pharmaceutiques
WO2013016580A2 (fr) * 2011-07-26 2013-01-31 University Of Southern California Inhibiteurs de monoamine oxydase et procédés pour le traitement et le diagnostic du cancer de la prostate
US20180177786A1 (en) * 2011-07-26 2018-06-28 University Of Southern California Monoamine oxidase inhibitors and methods for treatment and diagnosis of prostate cancer
US20180055915A1 (en) * 2016-03-11 2018-03-01 University Of Rochester Compositions and methods for treating prostate cancer

Non-Patent Citations (29)

* Cited by examiner, † Cited by third party
Title
ANGEW CHEM. INTL. ED. ENGL., vol. 33, 1994, pages 183 - 186
ANTONARAKIS ET AL., NEW ENGLAND JOURNAL OF MEDICINE, vol. 371, 2014, pages 1028 - 1038
ANTONARAKIS ET AL., THE NEW ENGLANDJOURNAL OF MEDICINE, vol. 371, 2014, pages 1028 - 1038
ARORA ET AL., CELL, vol. 155, 2013, pages 1309 - 1322
BUNDGARD: "Design of Prodrugs", vol. 7-9, 1985, ELSEVIER, pages: 21 - 24
C. LIU ET AL: "Niclosamide Inhibits Androgen Receptor Variants Expression and Overcomes Enzalutamide Resistance in Castration-Resistant Prostate Cancer", CLINICAL CANCER RESEARCH, vol. 20, no. 12, 16 April 2014 (2014-04-16), US, pages 1 - 21, XP055248432, ISSN: 1078-0432, DOI: 10.1158/1078-0432.CCR-13-3296 *
CHANG ET AL., ONCOGENE, vol. 33, 2014, pages 3225 - 3234
CHANG ET AL., SCIENCE, vol. 240, 1988, pages 324 - 326
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 915087-33-1
DHINGRA ET AL., MINI REV MED CHEM, vol. 13, 2013, pages 1475 - 1486
DORFMAN ET AL., CURRENT TOPICS IN BEHAVIORAL NEUROSCIENCES, vol. 17, 2014, pages 297 - 313
EMMANUEL S. ANTONARAKIS ET AL: "AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer", NEW ENGLAND JOURNAL OF MEDICINE, vol. 371, no. 11, 11 September 2014 (2014-09-11), pages 1028 - 1038, XP055566838, ISSN: 0028-4793, DOI: 10.1056/NEJMoa1315815 *
FLAMAND ET AL., JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, vol. 136, 2010, pages 1761 - 1771
HEINLEIN ET AL., ENDOCR REV, vol. 25, 2004, pages 276 - 308
JOSEPH ET AL., CANCER DISCOVERY, vol. 3, 2013, pages 1020 - 1029
KAISER, J., SCIENCE, vol. 324, 2009, pages 165
MERSEBURGER ET AL., THER ADV UROL, vol. 7, 2015, pages 9 - 21
MIYAMOTO ET AL., THE PROSTATE, vol. 61, 2004, pages 332 - 353
MIYAMOTO ET AL.: "Nature clinical practice", ONCOLOGY, vol. 2, 2005, pages 236 - 237
NIU ET AL., ONCOGENE, vol. 29, 2010, pages 3593 - 3604
RIEDERER ET AL., EXPERIMENTAL NEUROBIOLOGY, vol. 20, 2011, pages 1 - 17
RYAN ET AL., THE NEW ENGLANDJOURNAL OF MEDICINE, vol. 368, 2013, pages 1458 - 1459
SCHER ET AL., N ENGL J MED, vol. 367, 2012, pages 1187 - 1197
SCHER ET AL., NENGL J MED, vol. 367, 2012, pages 1187 - 1197
SHIKHA GAUR ET AL: "Effect of Monoamine oxidase A (MAOA) inhibitors on androgen-sensitive and castration-resistant prostate cancer cells", PROSTATE., vol. 79, no. 6, 28 January 2019 (2019-01-28), US, pages 667 - 677, XP055696637, ISSN: 0270-4137, DOI: 10.1002/pros.23774 *
SILVERMAN: "The Organic Chemistry of Drug Design and Drug Action", 1992, ACADEMIC PRESS, pages: 352 - 401
THOMAS SORRELL: "Organic Chemistry", 2006, UNIVERSITY SCIENCE BOOKS
WU ET AL., THE JOURNAL OF CLINICAL INVESTIGATION, vol. 124, 2014, pages 2891 - 2908
YEMELYANOV ET AL., CELL CYCLE, vol. 11, 2012, pages 395 - 406

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