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WO2024059951A1 - Inhibiteurs du domaine de liaison à l'adn du récepteur des androgènes - Google Patents

Inhibiteurs du domaine de liaison à l'adn du récepteur des androgènes Download PDF

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Publication number
WO2024059951A1
WO2024059951A1 PCT/CA2023/051259 CA2023051259W WO2024059951A1 WO 2024059951 A1 WO2024059951 A1 WO 2024059951A1 CA 2023051259 W CA2023051259 W CA 2023051259W WO 2024059951 A1 WO2024059951 A1 WO 2024059951A1
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Prior art keywords
cancer
prostate
resistant
prostate cancer
androgen receptor
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PCT/CA2023/051259
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English (en)
Inventor
Artem Tcherkassov
Mariia RADAEVA
Nada LALLOUS
Fuqiang Ban
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University of British Columbia
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University of British Columbia
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    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
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    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • 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
    • C07D417/12—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 chain containing hetero atoms as chain links
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • this invention re- lates to inhibitors of androgen receptor (AR) activity that target the DNA-bindng do- main (DBD) and their use in the treatment of diseases associated with or mediated by AR.
  • AR androgen receptor
  • PCa prostate cancer
  • the inhibition of AR with small mole- cules that compete with natural androgens is one of the primary strategies in PC ther- apy along with androgen synthesis ablation through castration 7 .
  • PCa often relapses as a more aggressive castration-resistant PCa (CRPC) after it gains various mu- tations that confer resistance to common antiandrogen treatments 8-10 .
  • the mecha- nisms underlying such resistance include gain-of-function point mutations in the andro- gen-binding site (ABS) that prevent antagonistic action of the drugs as well as complete splicing of the ligand-binding domain (LBD) 10-13 .
  • ABS gain-of-function point mutations in the andro- gen-binding site
  • LBD ligand-binding domain
  • a well-characterized splice variant of AR V7 lacking the LBD was shown to activate gene expression of vari- ous oncogenes and drive the progression of PCa in an androgen-independent man- ner 14,15 .
  • NBD N-termi- nus domain
  • DBD DNA-binding domain
  • D 3 may be selected from Cl, F, CH 3 , and H.
  • a 2 and A 3 may join to form a 5 or 6 membered ring, wherein may
  • a method of inhibiting AR activity including administering a compound may have the structure of Formula II: II, wherein, Q 1 may be selected from H and CH 3 ; Q 2 may be selected from
  • G 4 may be selected from F, Cl, and Br
  • G 5 may be selected from F, Cl, and Br
  • G 6 may be selected from F, Cl, and Br
  • G 7 may be selected from F, Cl, and Br
  • G 8 may be selected from F, Cl, and Br
  • G 9 may be selected from F, Cl, and Br
  • G 10 may be selected from F, Cl, and Br
  • G 11 may be selected from F, Cl, and Br
  • G 12 may be selected from F, Cl, and Br
  • G 13 may be selected from F, Cl, and Br
  • G 14 may be selected from F, Cl, and Br.
  • a method of inhibiting AR activity including administering a compound may have the structure of one of Formulas III-VI: wherein, Q 3 may be selected from H and CH 3 ; Q 4 may be selected from H and CH 3 ; Q 5 may be selected from H and CH 3 ; Q 8 may be selected from H and CH 3 ; Q 6 and Q 7 may form a substituted six membered ring having the structure and Q 10 may form a substituted six membered ring having the structure selected from may be selected from , , may be selected from F, Cl, and Br; G 16 may be selected from F, Cl, and Br; G 17 may be selected from F, Cl, and Br; G 18 may be selected from F, Cl, and Br; G 19 may be selected from F, Cl, and Br; G 20 may be selected from F, Cl, and Br; G 21 may be selected from F, Cl, and Br; G 22 may be selected from F, Cl, and Br; G 23 may be selected from F, Cl, and Br;
  • Z 8 may be selected from D 3 may be selected from Cl, F, CH 3 , and H.
  • G 1 may be F.
  • G 2 may be F.
  • G 3 may be Cl.
  • G 4 may be F.
  • G 5 may be Cl.
  • G 6 may be Cl.
  • G 7 may be F.
  • G 8 may be Cl.
  • G 9 may be Br.
  • G 10 may be Cl.
  • G 11 may be F.
  • G 12 may be F.
  • G 13 may be F.
  • G 14 may be Cl.
  • G 15 may be Cl.
  • G 16 may be Cl.
  • G 17 may be Cl.
  • G 18 may be Br.
  • G 19 may be Br.
  • G 20 may be Cl.
  • G 21 may be Cl.
  • G 22 may be Cl.
  • G 23 may be Cl.
  • G 24 may be Cl.
  • G 25 may be F.
  • G 26 may be Cl.
  • G 27 may be Br.
  • G 28 may be F.
  • the inhibition of the androgen receptor may be for the treatment of cancer.
  • the inhibition of the androgen receptor may be for the treatment of one or more of the following: cervical cancer; small-cell lung cancer; testicular cancer; carcinoma; neuroblastoma; osteosarcoma; glioblastoma; melanoma; lymphoma; leukemia; esophageal cancer; stomach cancer; colon cancer; breast cancer; ovarian cancer; endometrial cancer; chondrosarcomas; central nervous system cancer; liver cancer; prostate cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, Kennedy’s disease, and age-related macular degeneration.
  • the prostate cancer may be selected from: Neuroendocrine Prostate Cancer (NEPC); Prostate Adenocarcinoma; castration resistant prostate cancer (CRPC); androgen receptor pathway inhibitor (ARPI) resistant prostate cancer; enzalutamide (ENZ)- resistant (ENZ R ); and Abiraterone (Abi)-resistant (ABI R ).
  • NEPC Neuroendocrine Prostate Cancer
  • CRPC castration resistant prostate cancer
  • ARPI androgen receptor pathway inhibitor
  • ENZ enzalutamide
  • ENZ R enzalutamide
  • ABSI R Abiraterone
  • the compound may be selected from one or more of the following: The compound may be selected from and .
  • a pharmaceutical composition including compound of Formulas I-VI and a pharmaceutically acceptable carrier, for the treatment of one or more of the following: cervical cancer; small-cell lung cancer; testicular cancer; carcinoma; neuroblastoma; osteosarcoma; glioblastoma; melanoma; lymphoma; leukemia; esophageal cancer; stomach cancer; colon cancer; breast cancer; ovarian cancer; endometrial cancer; chondrosarcomas; central nervous system cancer; liver cancer; prostate cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, Kennedy’s disease, and age-related macular degeneration.
  • a pharmaceutical composition including compound of Formulas I-VI and a pharmaceutically acceptable carrier, for the treatment of prostate cancer which may be selected from: Neuroendocrine Prostate Cancer (NEPC); Prostate Adenocarcinoma; castration resistant prostate cancer (CRPC); androgen receptor pathway inhibitor (ARPI) resistant prostate cancer; enzalutamide (ENZ)-resistant (ENZ R ); and Abiraterone (Abi)-resistant (ABIR).
  • NEPC Neuroendocrine Prostate Cancer
  • Prostate Adenocarcinoma Prostate Adenocarcinoma
  • castration resistant prostate cancer CRPC
  • ARPI anti- receptor pathway inhibitor
  • ENZ enzalutamide
  • ENZ R enzalutamide-resistant
  • Abi Abiraterone
  • a commercial package comprising (a) a compound of any one of Formulas I-VI and a pharmaceutically acceptable carrier; and (b) instructions for the use thereof for treating one or more of the following: cervical cancer; small-cell lung cancer; testicular cancer; carcinoma; neuroblastoma; osteosarcoma; glioblastoma; melanoma; lymphoma; leukemia; esophageal cancer; stomach cancer; colon cancer; breast cancer; ovarian cancer; endometrial cancer; chondrosarcomas; central nervous system cancer; liver cancer; prostate cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, Kennedy’s disease, and age-related macular degeneration.
  • a commercial package comprising (a) a pharmaceutical composition comprising a compound of any one of Formulas I-VI and a pharmaceutically acceptable carrier; and (b) instructions for the use thereof for treating prostate cancer.
  • a use of a compound having the structure of Formulas I-VI as described herein for the manufacture of a medicament for inhibiting AR activity is provided.
  • the compound may be for use in the treatment of at least one indication selected from the group including: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, Kennedy’s disease, and age-related macular degeneration.
  • the inhibiting AR activity may be for the treatment of at least one indication selected from the group including: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, Kennedy’s disease, and age-related macular degeneration.
  • FIGURE 1 shows in silico screening against P-box and D-box on the surface of the Androgen Receptor (AR) DNA Binding Domain (DBD), where A shows tha AR DBD dimer with P-box with VPC-14449 docked and D-box with VPC-17005 docked shaded and DNA ribbon interacting with the P-box; B shows a schematic of the in silico screening pipeline workflow, indicating the number of D-box and P-box compounds after each step in the workflow pipeline; C shows the pharmacophore model built to select compounds for the D-box and was based on the common features of VPC-17005, VPC-17160, VPC-17121, and VPC-17281; and D shows the pharmacophore model built to select compounds for the P-box and was based on the common features of VPC- 14449.
  • A shows tha AR DBD dimer with P-box with VPC-14449 docked and D-box with VPC-17005 docked shaded and DNA ribbon
  • FIGURE 2 shows two compounds identifed through the in silico screening, VPC-14668 and VPC-17493, that were further tested for inhibiting the transcriptional activity of AR full length and AR-V7.
  • B shows the inhibition of AR full-length transcriptional activity in reporter eGFP assay in LNCaP cells.
  • C shows the inhibition of AR V7 transcriptional activity in reporter eGFP assay in PC3 cells.
  • D shows the direct effects on Nanoluciferase expression in a PC3 cell line transfected with Nanoluciferase and lacking AR.
  • E shows the inhibition of AR-regulated PSA expression in LNCaP cells. Data points represent a pool of triplicate for each concentration.
  • FIGURE 3 shows ligand-protein interactions of VPC-14668 (left) and VPC-17493 (right), with hydrophobic residues Pro 613, Ala 587 and Phe 583 in A and Ala 597, Pro 613, and Leu 595 in B, with polar residues Gln 592, Tyr 594, Arg 586, Arg 609, Ser 579Arg 616, and Lys 610 in A, and Arg 608, Asn 611, Thr 603, Cys 602 Ser 598 and Cys 612 in B, while the shading respresents solvent exposed areas.
  • DETAILED DESCRIPTION The following detailed description will be better understood when read in conjunction with the appended figures.
  • COOH and NR2 may include the corre- sponding ions, for example carboxylate ions and ammonium ions, respectively. Alter- natively, where the ions are shown, a person of skill in the art will appreciate that the counter ion may also be present.
  • the point of covalent attachment of the moi- ety to the compounds as described herein may be, for example, and without limitation, cleaved under specified conditions.
  • Specified conditions may include, for example, and without limitation, in vivo enzymatic or non-enzymatic means.
  • Cleavage of the moiety may occur, for example, and without limitation, spontaneously, or it may be cat- alyzed, induced by another agent, or a change in a physical parameter or environmental parameter, for example, an enzyme, light, acid, temperature or pH.
  • the moiety may be, for example, and without limitation, a protecting group that acts to mask a functional group, a group that acts as a substrate for one or more active or passive transport mech- anisms, or a group that acts to impart or enhance a property of the compound, for exam- ple, solubility, bioavailability or localization.
  • compounds of Formulas I-VI may be used for systemic treatment of at least one indication selected from the group consisting of: cervical cancer; small-cell lung cancer; testicular cancer; carcinoma; neuroblastoma; os- teosarcoma; glioblastoma; melanoma; lymphoma; leukemia; esophageal cancer; stom- ach cancer; colon cancer; breast cancer; ovarian cancer; endometrial cancer; chondro- sarcomas; central nervous system cancer; liver cancer; and prostate cancer.
  • the compounds of Formulas II and III may be used for systemic treatment of at least one indication selected from the group consisting of:prostate cancer; breast can- cer; colon cancer; cervical cancer; small-cell lung carcinoma; neuroblastomas; osteosar- coma; glioblastoma; melanoma; and myeloid leukaemia.
  • com- pounds of Formulas II and III may be used in the preparation of a medicament or a com- position for systemic treatment of an indication described herein.
  • methods of systemically treating any of the indications described herein are also provided.
  • Compounds as described herein may be in the free form or in the form of a salt thereof.
  • compounds as described herein may be in the form of a pharma- ceutically acceptable salt, which are known in the art (Berge S. M. et al., J. Pharm. Sci. (1977) 66(1):1-19).
  • Pharmaceutically acceptable salt as used herein includes, for ex- ample, salts that have the desired pharmacological activity of the parent compound (salts which retain the biological effectiveness and/or properties of the parent com- pound and which are not biologically and/or otherwise undesirable).
  • Compounds as described herein having one or more functional groups capable of forming a salt may be, for example, formed as a pharmaceutically acceptable salt.
  • Compounds containing one or more basic functional groups may be capable of forming a pharmaceutically ac- ceptable salt with, for example, a pharmaceutically acceptable organic or inorganic acid.
  • Pharmaceutically acceptable salts may be derived from, for example, and without limita- tion, acetic acid, adipic acid, alginic acid, aspartic acid, ascorbic acid, benzoic acid, ben- zenesulfonic acid, butyric acid, cinnamic acid, citric acid, camphoric acid, camphorsul- fonic acid, cyclopentanepropionic acid, diethylacetic acid, digluconic acid, dodecyl- sulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, glucoheptanoic acid, glu- conic acid, glycerophosphoric acid, glycolic acid, hemisulfonic acid, heptanoic acid, hexa- noic
  • Compounds containing one or more acidic func- tional groups may be capable of forming pharmaceutically acceptable salts with a phar- maceutically acceptable base, for example, and without limitation, inorganic bases based on alkaline metals or alkaline earth metals or organic bases such as primary amine compounds, secondary amine compounds, tertiary amine compounds, quater- nary amine compounds, substituted amines, naturally occurring substituted amines, cy-hack amines or basic ion-exchange resins.
  • a phar- maceutically acceptable base for example, and without limitation, inorganic bases based on alkaline metals or alkaline earth metals or organic bases such as primary amine compounds, secondary amine compounds, tertiary amine compounds, quater- nary amine compounds, substituted amines, naturally occurring substituted amines, cy-hack amines or basic ion-exchange resins.
  • Pharmaceutically acceptable salts may be derived from, for example, and without limitation, a hydroxide, carbonate, or bicar- bonate of a pharmaceutically acceptable metal cation such as ammonium, sodium, po- tassium, lithium, calcium, magnesium, iron, zinc, copper, manganese or aluminum, am- monia, benzathine, meglumine, methylamine, dimethylamine, trimethylamine, ethyla- mine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, etha- nolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclo- hexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylene- diamine, glucosamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine
  • compounds as described herein may contain both acidic and basic groups and may be in the form of inner salts or zwit- terions, for example, and without limitation, betaines.
  • Salts as described herein may be prepared by conventional processes known to a person skilled in the art, for exam- ple, and without limitation, by reacting the free form with an organic acid or inorganic acid or base, or by anion exchange or cation exchange from other salts. Those skilled in the art will appreciate that preparation of salts may occur in situ during isolation and purification of the compounds or preparation of salts may occur by separately reacting an isolated and purified compound.
  • compounds and all different forms thereof e.g.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent in physical association the compound or salt thereof.
  • the sol- vent may be, for example, and without limitation, a pharmaceutically acceptable solvent.
  • hydrates are formed when the solvent is water or alcoholates are formed when the solvent is an alcohol.
  • compounds and all different forms thereof e.g.
  • free forms, salts, solvates, isomeric forms) as described herein may include crystalline and amorphous forms, for example, polymorphs, pseudopolymorphs, conformational polymorphs, amorphous forms, or a combination thereof.
  • Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Poly- morphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and/or solubility. Those skilled in the art will appreciate that various factors includ- ing recrystallization solvent, rate of crystallization and storage temperature may cause a single crystal form to dominate. In some embodiments, compounds and all different forms thereof (e.g.
  • compositions as described herein may comprise a salt of such a compound, preferably a pharmaceutically or physiologically acceptable salt.
  • compositions will typically comprise one or more carriers, excipi- ents or diluents acceptable for the mode of administration of the preparation, be it by injection, inhalation, topical administration, lavage, or other modes suitable for the se- lected treatment.
  • Suitable carriers, excipients or diluents are those known in the art for use in such modes of administration.
  • Suitable pharmaceutical compositions may be formulated by means known in the art and their mode of administration and dose determined by the skilled practitioner.
  • a compound may be dissolved in sterile water or saline or a pharmaceutically acceptable vehicle used for administration of non-water soluble com- pounds such as those used for vitamin K.
  • the compound may be administered in a tablet, capsule or dissolved in liquid form.
  • the tablet or cap- sule may be enteric coated, or in a formulation for sustained release.
  • Many suitable formulations are known, including, polymeric or protein microparticles encapsulating a compound to be released, ointments, pastes, gels, hydrogels, or solutions which can be used topically or locally to administer a compound.
  • a sustained release patch or im- plant may be employed to provide release over a prolonged period of time. Many techniques known to one of skill in the art are described in Remington: the Science & Practice of Pharmacy by Alfonso Gennaro, 20th ed., Lippencott Williams & Wilkins, (2000).
  • Formulations for parenteral administration may, for example, contain excipi- ents, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydro- genated naphthalenes.
  • polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydro- genated naphthalenes.
  • Biocompatible, biodegradable lactide polymer, lactide/gly- colide copolymer, or polyoxyethylene polyoxypropylene copolymers may be used to control the release of the compounds.
  • Other potentially useful parenteral delivery systems for modulatory compounds include ethylene vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inha- lation may contain excipients, for example, lactose, or may be aqueous solutions con- taining, for example, polyoxyethylene 9 lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
  • Compounds or pharmaceutical compositions as described herein or for use as described herein may be administered by means of a medical device or appliance such as an im- plant, graft, prosthesis, stent, etc.
  • implants may be devised which are intended to contain and release such compounds or compositions.
  • An example would be an im- plant made of a polymeric material adapted to release the compound over a period of time.
  • an “effective amount” of a pharmaceutical composition as described herein includes a therapeutically effective amount or a prophylactically effective amount.
  • a “therapeu- tically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as reduced tumor size, increased life span or increased life expectancy.
  • a therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic re- sponse.
  • a therapeutically effective amount is also one in which any toxic or detri- mental effects of the compound are outweighed by the therapeutically beneficial effects.
  • a “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as smaller tu- mors, increased life span, increased life expectancy or prevention of the progression of prostate cancer to an androgen independent form.
  • a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effec- tive amount may be less than a therapeutically effective amount.
  • dosage values may vary with the severity of the condition to be al- leviated. For any particular subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person ad- ministering or supervising the administration of the compositions.
  • Dosage ranges set forth herein are exemplary only and do not limit the dosage ranges that may be selected by medical practitioners.
  • the amount of active compound(s) in the composition may vary according to factors such as the disease state, age, sex, and weight of the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be adminis- tered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It may be advantageous to formulate par- enteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • compounds and all different forms thereof as described herein may be used, for example, and without limitation, in combination with other treatment methods for at least one indication selected from the group consisting of: cervical can- cer; small-cell lung cancer; testicular cancer; carcinoma; neuroblastoma; osteosarcoma; glioblastoma; melanoma; lymphoma; leukemia; esophageal cancer; stomach cancer; co- lon cancer; breast cancer; ovarian cancer; endometrial cancer; chondrosarcomas; cen- tral nervous system cancer; liver cancer; and prostate cancer.
  • the com- pounds described herein may be useful for the treatment of one or more of the follow- ing: cervical cancer, small-cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, colon cancer, breast cancer, ovarian cancer, endo- metrial cancer, chondrosarcomas, central nervous system cancer, liver cancer and pros- tate cancer.
  • compounds and all their different forms as described herein may be used as neo-adjuvant (prior), adjunctive (during), and/or adjuvant (after) ther- apy with surgery, radiation (brachytherapy or external beam), or other therapies (for example, HIFU).
  • the compounds described herein may be administered with or combined with known chemotherapeutic treatments.
  • a com- pound of any one of Formulas I-VI may be administered in combination with taxols and Topoisomerase poisons, as well as in combination with androgen receptor (AR) thera- pies (for example, ADT, ARPIs, etc.) for prostate cancer (PCa).
  • AR androgen receptor
  • compounds as described herein should be used without causing substantial toxicity.
  • Toxicity of the compounds as described herein can be determined using standard techniques, for example, by testing in cell cultures or experimental animals and determining the therapeutic index, i.e., the ratio between the LD50 (the dose lethal to 50% of the population) and the LD100 (the dose lethal to 100% of the population). In some circumstances however, such as in severe disease conditions, it may be appro- priate to administer substantial excesses of the compositions. Some compounds as described herein may be toxic at some concentrations. Titration studies may be used to determine toxic and non-toxic concentrations. Toxicity may be evaluated by exam- ining a particular compound’s or composition’s specificity across cell lines using PC3 cells as a negative control that do not express AR.
  • a “subject” may be a human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc.
  • the subject may be suspected of having or at risk for having a cancer, such as cervical cancer; small-cell lung cancer; testicular cancer; carcinoma; neuroblas- toma; osteosarcoma; glioblastoma; melanoma; lymphoma; leukemia; esophageal can- cer; stomach cancer; colon cancer; breast cancer; ovarian cancer; endometrial cancer; chondrosarcomas; central nervous system cancer; liver cancer; and prostate cancer.
  • a cancer such as cervical cancer; small-cell lung cancer; testicular cancer; carcinoma; neuroblas- toma; osteosarcoma; glioblastoma; melanoma; lymphoma; leukemia; esophageal can- cer; stomach cancer; colon cancer; breast cancer; ovarian cancer; endometrial cancer; chondrosarcomas; central nervous system cancer; liver cancer; and prostate cancer.
  • a cancer such as cervical cancer; small-cell lung cancer; testicular
  • Diagnostic methods for various cancers such as cervical cancer, small-cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, colon can- cer, breast cancer, ovarian cancer, endometrial cancer, chondrosarcomas, central nerv- ous system cancer, liver cancer and prostate cancer, are known to those of ordinary skill in the art. All compounds specifically described herein are commercially available. Further- more, modifications to those compounds would be possible based on the knowledge of a person of skill in the art. Various alternative embodiments and examples are described herein. These embodi- ments and examples are illustrative and should not be construed as limiting the scope of the invention.
  • the docking with ICM was performed using a thoroughness of 5. DeepDockingTM was set to run for 5 iterations with other steps as outlined in the protocol publication 33 . Pharmacophore model development and screening were also performed using MOE software 34 .
  • Molecular dynamicsTM (MD) were performed using Desmond package from SchrodingerTM 35 .
  • the system was build using the OPLS3e force field 37 .
  • the simulations were carried out with 2-femtosecond time step using constant-pressure (NPT) ensem- ble at 300K and pressure of 1.03 bar.
  • NPT constant-pressure
  • PCa cell lines LNCaP (ATCC, CRL-1740) and PC-3 (ATCC, CRL-1435) cells were obtained in 2013 and authenticated by IDEXX LaboratoriesTM every 6 months. The cell lines are tested for mycoplasma contamination every two weeks. Reporter assays and cell viability experiments LNCaP cells incorporating an AR2PB-eGFP reporter construct (2 x probasin) are previ- ously described 38 . eGFP and secreted PSA assays were performed as described 18,38 . PC3_iV7 + 3TKNLuc cell line generation is previously described 21 .
  • NanoluciferaseTM reporter assays were performed by treating the cells with 200ng/mL Doxycycline and compounds overnight, and cell lysis with Nano-Glo LuciferaseTM reagent (PromegaTM). Luminescence detection was carried out on a TECAN m200proTM luminometer.
  • CID computer- aided drug design
  • VPC-17005, VPC-17160, VPC-17121, and VPC-17281) and derived a pharmacophore model containing two aromatic features and one hydro- gen bond acceptor (FIGURE 1D).
  • FOGURE 1D hydro- gen bond acceptor
  • Example 2 Selected Compounds Reduce AR Full Length and AR V7 Transcrip- tional Activity The purchased compounds were first tested for inhibition of full-length AR transcrip- tional activity.
  • the AR-enhanced green fluorescent protein (eGFP) assay was per- formed in LNCaP cells, where an androgen-inducible probation-derived promoter con- trols the expression of eGFP 38 . From P-box selection, 23 compounds showed more than 50% inhibition at 10 ⁇ M concentration while from D-box, 54 compounds passed the threshold. Thus, given that we tested 160 and 270 compounds from each selec- tion, respectively, hit rates from the initial screening were roughly equal to 14% and 20%. Then, we performed dose-dependent titration against a full-length AR eGFP as- say. The IC 50 s for 18 compounds that produced a smooth downward curve ranged from 0.28 to 26.8 ⁇ M.
  • Hit compounds VPC-17493 and VPC-14668 exhibited an IC50 of 0.28 and 0.9, respectively (FIGURE 2A, B).
  • a nanoluciferase assay on the AR V7 splice variant with two of the AR inhibitory compounds. The assay was performed in PC3 cells transfected with AR-V7 cDNA and the ARR3tk-nanoLuciferase reporter construct. Whereby the activation of nanoluciferase was an indication AR-V7 transcriptional activity.
  • Two compounds, VPC-17493 and VPC-14668 exhibited complete inhibition of AR V7 tran- scriptional activity at 10 ⁇ M.
  • VPC-14668 and VPC-17493 reduced the levels of PSA, a PCa biomarker, in a PCa cell line.
  • PSA a PCa biomarker
  • the reduction in PSA levels indicates successful inhibition of AR signaling.
  • CADD techniques enables finding novel chemotypes with desired bioactivi- ties and further adds to the growing body of research advocating for ultra-large screen- ings in drug discovery 26,27,46,47 .
  • Both of the identified hits, VPC-14668 and VPC-17493 represent unexplored chemical scaffolds that are not present in the standard ‘in-stock’ libraries of the ZINC20 database 31 .
  • the P-box targeting compound VPC- 14668 forms a strong hydrogen bond with Tyr594 (-2.1 kcal/mol) through oxygen atom in a similar manner to VPC-14449’s morpholine ring 18 .
  • this bond was conserved throughout 70% of a 50ns molecular dynamics simulation illustrating the im- portance of the bond. This observation is in agreement with the previously identified loss of activity of compounds VPC-14449 in mutant Tyr594Asp AR DBD 18 . Therefore, we conclude that hydrogen bonding with Tyr594 is an important binding feature for AR DBD inhibition at P-box.
  • residue Tyr594 is likely to be a so-called ‘hot- spot’ residue (i.e.
  • VPC-17493 further proves our binding hypothesis for disruption of AR dimerization where an amide group bound to the zinc atom is an important binding feature.
  • ZINC20 a free ultralarge-scale chemical database for ligand discovery. Journal of chemical information and modeling 60, 6065-6073 (2020). 32 Hawkins, P. C., Skillman, A. G., Warren, G. L., Ellingson, B. A. & Stahl, M. T. Conformer generation with OMEGA: algorithm and validation using high quality structures from the Protein Databank and Cambridge Structural Database. Journal of chemical information and modeling 50, 572-584 (2010). 33 Gentile, F. et al. Artificial intelligence–enabled virtual screening of ultra-large chemical libraries with deep docking. Nature Protocols 17, 672-697 (2022). 34 Molecular Operating Environment (MOE) (Chemical Computing Group (ULC), 2019).
  • MOE Molecular Operating Environment
  • AutoDock4 and AutoDockTools4 Automated docking with selective receptor flexibility. Journal of computational chemistry 30, 2785-2791 (2009). 42 Palacio-Rodr ⁇ guez, K., Lans, I., Cavasotto, C. N. & Cossio, P. Exponential consensus ranking improves the outcome in docking and receptor ensemble docking. Scientific reports 9, 1-14 (2019). 43 Houston, D. R. & Walkinshaw, M. D. Consensus docking: improving the reliability of docking in a virtual screening context. Journal of chemical information and modeling 53, 384-390 (2013).44 Dhanasekaran, S. M. et al. Delineation of prognostic biomarkers in prostate cancer.

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Abstract

La présente invention concerne un composé ayant une structure de formules I-VI. L'invention concerne par ailleurs des utilisations de tels composés pour le traitement de diverses indications pour lesquelles une modulation du récepteur des androgènes serait bénéfique, comme le cancer de la prostate. L'invention concerne également des procédés de traitement et des utilisations des composés représentés par les formules I-VI.
PCT/CA2023/051259 2022-09-22 2023-09-22 Inhibiteurs du domaine de liaison à l'adn du récepteur des androgènes Ceased WO2024059951A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1553074A1 (fr) * 2002-08-12 2005-07-13 Takeda Pharmaceutical Company Limited Derive de benzene a cycles accoles et son utilisation
US20070004679A1 (en) * 2004-05-17 2007-01-04 Nathalie Schlienger Androgen receptor modulators and methods of treating disease using the same
WO2015120543A1 (fr) * 2014-02-14 2015-08-20 The University Of British Columbia Composés ciblant le domaine de liaison à l'adn (dbd) du récepteur des androgènes humain servant d'agents thérapeutiques et procédés pour leur utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1553074A1 (fr) * 2002-08-12 2005-07-13 Takeda Pharmaceutical Company Limited Derive de benzene a cycles accoles et son utilisation
US20070004679A1 (en) * 2004-05-17 2007-01-04 Nathalie Schlienger Androgen receptor modulators and methods of treating disease using the same
WO2015120543A1 (fr) * 2014-02-14 2015-08-20 The University Of British Columbia Composés ciblant le domaine de liaison à l'adn (dbd) du récepteur des androgènes humain servant d'agents thérapeutiques et procédés pour leur utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TRUMP, R.P. ET AL.: "Design and Synthesis of an Array of Selective Androgen Receptor Modulators", J. COMB. CHEM., vol. 9, 2007, pages 107 - 114, XP008133518, DOI: 10.1021/cc060096e *

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