COMPOSITIONS AND METHODS FOR TREATING EZH2-MEDIATED CANCER
Methods for designing bivalent compounds which selectively degrade/disrupt EZH2 and compositions and methods of using such degraders/disruptors to treat EZH2-mediated cancer are provided.
1 . A bivalent compound comprising an enhancer of zeste homologue 2 (EZH2) ligand conjugated to a degradation/disruption tag.
2 . The bivalent compound of claim 1 , wherein the EZH2 ligand is an EZH2 inhibitor.
3 . The bivalent compound of claim 2 , wherein the EZH2 ligand is selected from the group consisting of UNC1999, EPZ005687, EPZ-6438, GSK126, EI1, CPI-1205, GSK343, CPI-360, EPZ011989, compound 24, compound 3, compound 31, ZLD1039, PF-06821497, JQEZ5, and analogs thereof.
4 . The bivalent compound of any one of claims 1 to 3 , wherein the degradation/disruption tag is selected from the group consisting of adamantane, 1-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonane, pomalidomide, thalidomide, lenalidomide, VHL-1, and analogs thereof.
5 . The bivalent compound of any one of claims 1 to 4 , wherein the degradation/disruption tag binds to a ubiquitin ligase or mimics EZH2 protein misfolding.
6 . The bivalent compound of claim 5 , wherein the ubiquitin ligase is an E3 ligase.
7 . The bivalent compound of claim 6 , wherein the E3 ligase is selected from the group consisting of cereblon E3 ligase and VHL E3 ligase.
8 . The bivalent compound of claim 5 , wherein the degradation/disruption tag that mimics EZH2 protein misfolding comprises a hydrophobic group.
9 . The bivalent compound of any one of claims 1 - 8 , wherein the EZH2 ligand is conjugated to the degradation/disruption tag through a linker.
10 . The bivalent compound of claim 9 , wherein the linker comprises an acyclic or cyclic saturated or unsaturated carbon, ethylene glycol, amide, amino, ether, or carbonyl containing group.
11 . The bivalent compound of claim 9 or 10 , wherein the linker is selected from the group consisting of:
12 . The bivalent compound of claim 9 or 10 , wherein the linker is:
wherein R is independently —CH 2 —; —CF 2 —; —CH(C 1-3 alkyl)-; —C(C 1-3 alkyl)(C 1-3 alkyl)-;
—CH═CH—; —C(C 1-3 alkyl)═C(C 1-3 alkyl)-; —C≡C—; —O—; —NH—; —N(C 1-3 alkyl)-;
—C(O)NH—; —C(O)N(C 1-3 alkyl)-; or a 3-13 membered ring, a fused ring, a bridged ring, or a spiro ring with or without one or more heteroatoms selected from the group consisting of —NH—, —N(C 1-3 alkyl)-, and —O—;
X and Y are independently O or H 2 ; and
m and n are independently 0-15.
13 . The bivalent compound of claim 12 , wherein R is selected from the group consisting of:
wherein X′ and Y′ are independently N or CH, and m, n, o, and p are independently 0-5;
or the group consisting of:
wherein A, B, C, and D are independently CH, C(C 1-3 alkyl), or N, and
wherein A, B, C, D, and E are independently CH, C(C 1-3 alkyl), N, NH, N(C 1-3 alkyl), O, or S.
14 . The bivalent compound of any of claims 1 - 13 , wherein the bivalent compound is selected from the group consisting of AM16-10A, AM16-11A, AM16-37A, AM16-38A, XY019-43, XY019-44, XY019-079, XY019-080, AM16-91A, AM16-92A, AM16-93A, AM16-97A, AM16-100A, AM16-101A, AM16-102A, AM16-105A, AM16-106A, XY012-120, AM29-21A, AM29-22A, AM29-32A, AM29-33A, AM16-103A, AM29-182A, AM29-55A, AM29-151A, AM29-152A, AM29-137A, AM29-153A, AM29-138A, AM29-154A, AM29-139A, AM29-155A, AM29-170A, AM29-156A, AM29-171A, AM29-157A, AM29-172A, AM29-173A, AM16-79A, AM29-177A, AM29-141A, AM29-178A, AM29-142A, AM29-179A, AM29-143A, AM29-180A, AM29-144A, AM29-145A, AM29-181A, AM41-16A, AM41-17A, AM41-18A, XY012-157, XF034-164A, XF034-165A, XF034-166A, XF034-167A, XF034-168A, XY019-041, XF034-169A, XF034-170A, XF034-171A, CZ40-10, CZ40-09, CZ40-11, XY019-077, XY019-083, XY019-084, XF034-172A, XF034-173A, XF034-174A, XF034-175A, XF034-176A, XF034-177A, YS36-48, YS36-49, YS36-50, YS36-51, YS36-52, YS36-53, YS36-54, YS36-55, YS36-56, YS36-57, YS36-58, YS36-59, XY028-086, CZ40-72, CZ40-73, CZ40-75, CZ40-149, CZ40-74, CZ40-131, AM41-36A, AM41-37A, AM41-39A, AM41-41A, AM41-38A, AM41-40A, XF042-84, XF042-85, XF042-95, XF042-132, XF042-86, XF042-94, XF042-89, XF042-90, XF042-93, XF042-133, XF042-91, and XF042-92.
15 . A bivalent compound selected from the group consisting of AM16-10A, AM16-11A, AM16-37A, AM16-38A, XY019-43, XY019-44, XY019-079, XY019-080, AM16-91A, AM16-92A, AM16-93A, AM16-97A, AM16-100A, AM16-101A, AM16-102A, AM16-105A, AM16-106A, XY012-120, AM29-21A, AM29-22A, AM29-32A, AM29-33A, AM16-103A, AM29-182A, AM29-55A, AM29-151A, AM29-152A, AM29-137A, AM29-153A, AM29-138A, AM29-154A, AM29-139A, AM29-155A, AM29-170A, AM29-156A, AM29-171A, AM29-157A, AM29-172A, AM29-173A, AM16-79A, AM29-177A, AM29-141A, AM29-178A, AM29-142A, AM29-179A, AM29-143A, AM29-180A, AM29-144A, AM29-145A, AM29-181A, AM41-16A, AM41-17A, AM41-18A, XY012-157, XF034-164A, XF034-165A, XF034-166A, XF034-167A, XF034-168A, XY019-041, XF034-169A, XF034-170A, XF034-171A, CZ40-10, CZ40-09, CZ40-11, XY019-077, XY019-083, XY019-084, XF034-172A, XF034-173A, XF034-174A, XF034-175A, XF034-176A, XF034-177A, YS36-48, YS36-49, YS36-50, YS36-51, YS36-52, YS36-53, YS36-54, YS36-55, YS36-56, YS36-57, YS36-58, YS36-59, XY028-086, CZ40-72, CZ40-73, CZ40-75, CZ40-149, CZ40-74, CZ40-131, AM41-36A, AM41-37A, AM41-39A, AM41-41A, AM41-38A, AM41-40A, XF042-84, XF042-85, XF042-95, XF042-132, XF042-86, XF042-94, XF042-89, XF042-90, XF042-93, XF042-133, XF042-91, and XF042-92.
16 . A method of treating an enhancer of zeste homologue 2 (EZH2)-mediated cancer, comprising administering to a subject in a subject in need thereof with an EZH2-mediated cancer a bivalent compound comprising an enhancer of zeste homologue 2 (EZH2) ligand conjugated to a degradation/disruption tag.
17 . The method of claim 16 , wherein the EZH2-mediated cancer overexpresses EZH2 relative to a wild-type tissue of the same species and tissue type.
18 . The method of claim 16 or 17 , wherein the EZH2-mediated cancer comprises hyper-trimethylated H3K27.
19 . The method of any of claims 16 - 18 , wherein the at least one bivalent compound is selected from the group consisting of AM16-10A, AM16-11A, AM16-37A, AM16-38A, XY019-43, XY019-44, XY019-079, XY019-080, AM16-91A, AM16-92A, AM16-93A, AM16-97A, AM16-100A, AM16-101A, AM16-102A, AM16-105A, AM16-106A, XY012-120, AM29-21A, AM29-22A, AM29-32A, AM29-33A, AM16-103A, AM29-182A, AM29-55A, AM29-151A, AM29-152A, AM29-137A, AM29-153A, AM29-138A, AM29-154A, AM29-139A, AM29-155A, AM29-170A, AM29-156A, AM29-171A, AM29-157A, AM29-172A, AM29-173A, AM16-79A, AM29-177A, AM29-141A, AM29-178A, AM29-142A, AM29-179A, AM29-143A, AM29-180A, AM29-144A, AM29-145A, AM29-181A, AM41-16A, AM41-17A, AM41-18A, XY012-157, XF034-164A, XF034-165A, XF034-166A, XF034-167A, XF034-168A, XY019-041, XF034-169A, XF034-170A, XF034-171A, CZ40-10, CZ40-09, CZ40-11, XY019-077, XY019-083, XY019-084, XF034-172A, XF034-173A, XF034-174A, XF034-175A, XF034-176A, XF034-177A, YS36-48, YS36-49, YS36-50, YS36-51, YS36-52, YS36-53, YS36-54, YS36-55, YS36-56, YS36-57, YS36-58, YS36-59, XY028-086, CZ40-72, CZ40-73, CZ40-75, CZ40-149, CZ40-74, CZ40-131, AM41-36A, AM41-37A, AM41-39A, AM41-41A, AM41-38A, AM41-40A, XF042-84, XF042-85, XF042-95, XF042-132, XF042-86, XF042-94, XF042-89, XF042-90, XF042-93, XF042-133, XF042-91, and XF042-92.
20 . The method of any of claims 16 - 19 , wherein the at least one bivalent compound is administered orally, parenterally, intradermally, subcutaneously, topically, or rectally.
21 . The method of any of claims 16 - 20 , further comprising treating the subject with one or more additional therapeutic regimens for treating cancer.
22 . The method of claim 21 , wherein the one or more additional therapeutic regimens are selected from the group consisting of surgery, chemotherapy, radiation therapy, hormone therapy, and immunotherapy.
23 . The method of any of claims 16 - 22 , wherein the EZH2-mediated cancer is selected from the group consisting of breast cancer, glioblastoma, prostate cancer, uterine cancer, ovarian cancer, pancreatic cancer, melanoma, renal cell carcinoma, bladder cancer, colorectal cancer, lymphoma, leukemia, malignant rhabdoid tumor, and oropharyngeal cancer.
24 . The method of claim 23 , wherein the breast cancer is triple-negative breast cancer (TNBC).
25 . The method of any of claims 16 - 24 , wherein the EZH2-mediated cancer is a relapsed cancer.
26 . The method of any of claims 16 - 25 , wherein the EZH2-mediated cancer was refractory to one or more previous treatments.
27 . A method for identifying a bivalent compound which mediates degradation/disruption of EZH2, the method comprising:
providing a bivalent test compound comprising an EZH2 ligand conjugated to a degradation/disruption tag;
contacting the bivalent test compound with a cell comprising a ubiquitin ligase and EZH2;
determining whether EZH2 levels decrease in the cell; and
identifying the bivalent test compound as a bivalent compound which mediates reduction of EZH2 if EZH2 levels decrease in the cell.
28 . The method of claim 27 , wherein the cell is a cancer cell.
29 . The method of claim 28 , wherein the cancer cell is an EZH2-mediated cancer cell.