US2019375732A1PendingUtilityA1
Anti-cancer nuclear hormone receptor-targeting compounds
Est. expiryMay 14, 2038(~11.8 yrs left)· nominal 20-yr term from priority
Inventors:David HungSon Minh PhamSarvajit ChakravartyJiyun ChenJayakanth KankanalaAnup BardeAnjan Kumar Nayak
A61K 47/545A61K 47/55A61K 47/554A61K 45/06C07D 401/14C07D 413/14C07D 417/14C07D 471/04C07D 487/04C07J 43/003A61P 35/00C07D 498/04C07D 519/00C07D 451/02C07D 491/048C07D 403/10C07D 403/14A61K 9/0053C07D 403/12C07D 237/32
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Claims
Abstract
The disclosure relates to anti-cancer compounds derived from nuclear steroid receptor binders, to products containing the same, as well as to methods of their use and preparation.
Claims
exact text as granted — not AI-modified1 . A compound comprising at least one nuclear payload and at least one nuclear receptor-targeting epitope; provided that when the compound comprises one nuclear payload and one nuclear receptor-targeting epitope:
the nuclear receptor-targeting epitope is not a peptide, protein, nanoparticle or antibody; and when the nuclear receptor-targeting epitope is an androgen receptor-targeting epitope or an estrogen receptor-targeting epitope, the nuclear payload is not doxorubicin, or an analog thereof, and is not a hydroxamic acid which binds histone deacetylase (HDAC).
2 . A compound comprising at least one nuclear payload which binds to a catalytic domain of poly(ADP-ribose) polymerase (PARP) and at least one nuclear receptor-targeting epitope.
3 . The compound of claim 1 , wherein at least one nuclear receptor-targeting epitope is a nuclear steroid receptor-targeting epitope.
4 . The compound of claim 1 , wherein the nuclear payload is bonded to one nuclear receptor-targeting epitope via a non-biocleavable linking moiety and one or more nuclear receptor-targeting epitope(s) via a biocleavable linking moiety.
5 . The compound of claim 1 , wherein the compound comprises at least one nuclear payload which binds to a protein involved in the DNA damage repair process.
6 . The compound of claim 1 , wherein the compound comprises at least one nuclear payload which binds poly(ADP-ribose) polymerase (PARP), DNA-dependent protein kinase (DNA-PK), histone deacetylase (HDAC), enhancer of zeste homolog 2 (EZH2), histone acetyl transferase (HAT), methyltransferase, a bromodomain, myelin transcription factor 1 (MYT1), p53, melanocyte-stimulating hormone (MSH), mutL homolog (MLH), ERCC1, apurinic/apyrimidinic endonuclease 1 (APE1), topoisomerase I (Topo I), topoisomerase II (Topo II), Wee1, checkpoint kinase1 (Chk1), checkpoint kinase2 (Chk2), ataxia telangiectasia (ATR), or ataxia-telangiectasia mutated (ATM).
7 . The compound of claim 1 , wherein the nuclear payload comprises olaparib (AZD-2281), Olaparib TOPARP-A, rucaparib (AGO 14699, PF-01367338), niraparib, talazoparib (BMN-673), veliparib (ABT-888), CEP 9722, E7016, BGB-290, 3-aminobenzamide, methoxyamine, CC-115, MSC2490484A, AZD6738, VX-970, AZD0156, GDC-0575, MK-8776, LY2606368, AZD1775, belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, topotecan, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide, vorinostat, romidepsin (Istodax), chidamide, panobinostat (Farydak), belinostat (PXD101), panobinostat (LBH589), valproic acid (as Mg valproate), mocetinostat (MGCDO 103), abexinostat (PCI-24781), entinostat (MS-275), SB939, resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), HBI-8000, kevetrin, CUDC-101, AR-42, CHR-2845, CHR-3996, 4SC-202, CG200745, ACY-1215, ME-344, sulforaphane, tazemetostat, MAK638, CPI-1205), DS-3201b, anacardic acid, MG149, C646, S-adenosyl methionine, JQ1, I-BET 151 (GSK1210151A), I-BET 762 (GSK525762), OTX-015, TEN-010, CPI-203, CPI-0610, olinone, LY294002, or an analog thereof.
8 . The compound of claim 2 , wherein the compound comprises at least one nuclear payload which binds to a catalytic domain of poly(ADP-ribose) polymerase (PARP).
9 . The compound of claim 2 , wherein the catalytic domain comprises a conserved HYE motif.
10 . The compound of claim 1 , wherein the compound comprises at least one nuclear payload which binds to a poly(ADP-ribose) polymerase (PARP) with an IC 50 of less than about 500 nM.
11 . The compound of claim 8 , wherein the PARP comprises PARP-1 and/or PARP-2, or a variant thereof.
12 . The compound of any-preceding claim 1 , wherein the compound is of Formula I or II:
A-(L-B) m I
A-L-(B) m II
wherein: A is a nuclear payload; m is 1, 2 or 3; each B is independently a nuclear receptor-targeting epitope; and each L is independently a covalent bond or a linking moiety.
13 . A compound of Formula III, IV, V or VI, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:
wherein:
each R 1 , R 2 , R 3 and R 4 is independently -L-(B) m , hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R 5 , —C(═O)OR 5 , —C(═O)NR 5 R 6 , —S(═O) 1-2 R 5 , —S(═O) 1-2 NR 5 R 6 , —NR 5 S(═O) 1-2 R 6 or —C═NOR 5 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R 1 , R 2 , R 3 and R 4 are independently optionally substituted with one or more R 10 as valency permits;
m is 1, 2, or 3;
each L is independently a covalent bond or a linking moiety;
each B is independently a nuclear receptor-targeting epitope;
each R 10 is independently halo, cyano, nitro, —OR 7 , —SR 7 , —SF 5 , —NR 7 R 8 , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R 7 , —C(═O)OR 7 , —OC(═O)OR 7 , —OC(═O)R 7 , —C(═O)NR 7 R 8 , —OC(═O)NR 7 R 8 , —NR 7 C(═O)NR 7 R 8 , —S(═O) 1-2 R 7 , —S(═O) 1-2 NR 7 R 8 , —NR 7 S(═O) 1-2 R 8 , —NR 7 S(═O) 1-2 NR 7 R 8 , —NR 7 C(═O)R 8 , —NR 7 C(═O)OR 8 or —C═NOR 7 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R 10 are independently optionally substituted with one or more halo or C 1-12 alkyl optionally substituted by oxo, halo, hydroxyl or amino as valency permits; and
each R 5 and R 6 is independently hydrogen, deuterium, C 1-12 alkyl or C 3-12 cycloalkyl, optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R 5 and R 6 are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C 1-12 alkyl optionally substituted by oxo, halo, hydroxyl or amino;
each R 7 and R 8 is independently hydrogen, deuterium or C 1-12 alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R 7 and R 8 are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C 1-12 alkyl optionally substituted by oxo, halo, hydroxyl or amino; and
R 9 is hydrogen or R 2 ;
provided that at least one R 1 , R 2 , R 3 and R 4 is -L-(B) m .
14 . A compound of Formula IIIB, IVA, VB or VIA, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:
wherein:
R 2 is -L-(B) m ;
m is 1, 2, or 3;
L is a covalent bond or a linking moiety; and
each B is independently a nuclear receptor-targeting epitope.
15 . The compound of claim 12 , wherein at least one L is a non-biocleavable linking moiety.
16 . The compound of claim 12 , wherein at least one L is an acid-labile linking moiety.
17 . The compound of claim 12 , wherein the linking moiety is alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene; wherein each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, may optionally comprise an arylene, heteroarylene, cycloalkylene or heterocycloalkylene; and further wherein each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene is independently optionally substituted with one to five substituents independently selected from oxo, halo, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkyl.
18 . The compound of claim 12 , wherein the linking moiety is of the formula:
—Y 1 —(CH 2 ) n′ —Y 2 —(CH 2 ) m′ —Y 3 —
wherein: each of Y 1 , Y 2 , and Y 3 are independently a bond, —NR 11 —, —O—, —S(O) 0-2 —, —NR 11 C(O)—, —C(O)NR 11 —, —NR 11 S(O) 2 —, —S(O) 2 NR 11 —, —CR 12 ═N—NR 11 —, —NR 11 —N═CR 12 —, —C(O)—, arylene, heteroarylene, cycloalkylene or heterocycloalkylene; wherein each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene is independently optionally substituted with one to five substituents independently selected from oxo, halo, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkyl; each R 11 is independently C 1-4 alkyl, C 1-4 haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; each R 12 is independently C 1-4 alkyl, C 1-4 haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and n′ and m′ are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.
19 . The compound of claim 12 , wherein at least one linking moiety comprises a hydrazone linkage.
20 . The compound of claim 1 , wherein the at least one nuclear receptor-targeting epitope is a nuclear steroid receptor-targeting epitope.
21 . The compound of claim 1 , wherein the at least one nuclear receptor-targeting epitope is independently selected from an estrogen receptor-targeting epitope, glucocorticoid receptor-targeting epitope, progesterone receptor-targeting epitope or androgen receptor-targeting epitope.
22 . The compound of claim 1 , wherein the at least one nuclear receptor-targeting epitope independently comprises an epitope derived from an androgen receptor agonist, an androgen receptor antagonist, a selective androgen-receptor modulator (SARM), an estrogen receptor agonist, an estrogen receptor antagonist, a selective estrogen receptor modulator (SERM), a glucocorticoid receptor antagonist, a glucocorticoid receptor agonist, a selective glucocorticoid receptor modulator (SGRM), a progesterone receptor antagonist, a progesterone receptor agonist, a selective progesterone receptor modulator (SPRM), or a combination thereof.
23 . The compound of claim 1 , wherein the at least one nuclear receptor-targeting epitope independently comprises an epitope derived from estrogen, estetrol, estriol, estrone, progesterone, enobosarm, bicalutamide, apalutamide, testosterone, dihydrotestosterone, estradiol, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, megestrol acetate, estramustine, abiraterone, LGD-2941, BMS-564929, ostarine, or an analog thereof.
24 . The compound of claim 1 , wherein at least one nuclear receptor-targeting epitope is capable of binding to a ligand binding domain of a nuclear steroid receptor.
25 . The compound of claim 24 , wherein the nuclear steroid receptor is an estrogen receptor, a glucocorticoid receptor, a progesterone receptor, or an androgen receptor.
26 . The compound of claim 1 , wherein the at least one nuclear receptor-targeting epitope binds to a nuclear steroid receptor with an IC 50 of less than about 500 nM or an EC 50 of less than about 1 μM.
27 . The compound of claim 1 , wherein the at least one nuclear receptor-targeting epitope is not a peptide, protein, nanoparticle or antibody.
28 . A compound as in claim 12 , selected from the group consisting of
29 . A pharmaceutical composition comprising a compound as in claim 1 and a pharmaceutically acceptable excipient.
30 . A method for the treatment or prevention of a condition which can be ameliorated by inhibition of PARP in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound or pharmaceutical composition of claim 1 or a pharmaceutically acceptable salt or solvate thereof.
31 . A method of treating or preventing cancer, comprising administering an effective amount of a compound or pharmaceutical composition of claim 1 or a pharmaceutically acceptable salt or solvate thereof to an individual in need thereof.
32 . The method of claim 30 , wherein the administering comprises oral administration.
33 . The method of claim 30 , further comprising administering an additional chemotherapeutic agent.
34 . The method of claim 33 , wherein the additional chemotherapeutic agent is cisplatin or etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, taxotere, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778123, BMS 214662, gefitinib, erlotinib hydrochloride, antibodies to EGFR, matinib, intron, cytarabine, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, vinblastine, vincristine, vindesine, bleomycin, doxorubicin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrolacetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, herceptin, bexxar, velcade, zevalin, trisenox, xeloda, vinorelbine, porfimer, cetuximab, liposomal, Thiotepa, Altretamine, melphalan, Trastuzumab, lerozole, fulvestrant, exemestane, ifosfomide, rituximab, C225, Campath, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP 16), tamoxifen, raloxifene, estrogen receptor binding agents, paclitaxel, gemcitabine, navelbine, farnesyl-protein transferase inhibitors, transplatinum, 5-fluorouracil, vincristine, vinblastine and methotrexate, or an analog or derivative thereof.
35 . The method of claim 31 , further comprising administering radiotherapy to the patient.
36 . The method of claim 31 , wherein the cancer is a BRCA positive cancer.
37 . The method of claim 31 , wherein the cancer is a solid tumor.
38 . The method of claim 31 , wherein the cancer is a cancer affecting B cells.
39 . The method of claim 31 , wherein the cancer is a blood cancer, lung cancer, breast cancer, fallopian tube cancer, brain cancer, head and neck cancer, esophageal cancer, ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer or skin cancer.
40 . The method of claim 39 , wherein the cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphomas, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, chronic lymphocytic leukemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, choriocarcinoma, mycosis fungoide, head neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, or prostatic carcinoma.
41 . The method of claim 39 , wherein the cancer is bladder cancer, breast cancer, fallopian tube cancer, ovarian cancer, prostate cancer, peritoneal cancer, testicular cancer, endometrial cancer, or uterine cancer.
42 . A method of treating or preventing an androgen receptor overexpressing cancer, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one nuclear payload and at least one androgen receptor-targeting epitope to an individual in need thereof.
43 . The method of claim 42 , wherein the cancer is prostate, breast, triple negative breast cancer, bladder, or liver cancer.
44 . The method of claim 42 , wherein the androgen receptor-targeting epitope comprises an androgen receptor agonist, a selective androgen-receptor modulator (SARM), an androgen receptor antagonist, a selective estrogen receptor modulator (SERM), an estrogen receptor antagonist, a progestin, or an estrogen.
45 . The method of claim 44 , wherein the androgen receptor-targeting epitope comprises enobosarm, bicalutamide, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, estramustine, ketoconazole, abiraterone, darolutamide, or an analog thereof.
46 . A method of treating or preventing an estrogen and/or progesterone receptor overexpressing cancer, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one nuclear payload and at least one estrogen and/or progesterone receptor-targeting epitope to an individual in need thereof.
47 . The method of claim 46 , wherein the cancer is breast, uterine, or ovarian cancer.
48 . A method of treating or preventing a glucocorticoid receptor overexpressing cancer, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one nuclear payload and at least one glucocorticoid receptor-targeting epitope to an individual in need thereof.
49 . The method of claim 48 , wherein the cancer is prostate, breast, uterine, or ovarian cancer.Join the waitlist — get patent alerts
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