SETD2 inhibitors and related methods and uses, including combination therapies
The present disclosure provides SETD2 protein inhibitors, and methods, compositions, and kits for treating diseases, disorders, or conditions in a subject with a SETD2 protein inhibitor and, optionally, a second therapeutic agent, wherein the second therapeutic agent comprises one or more glucocorticoid receptor agonists, one or more immunomodulatory drugs, one or more proteasome inhibitors, one or more Bcl-2 inhibitors, one or more pleiotropic pathway modulators, one or more XPO1 inhibitors, one or more histone deacetylase inhibitors, or one or more EZH2 inhibitors, or a combination thereof.
1 . A method of treating multiple myeloma or mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject:
(a) a compound of Formula IV-A:
Z 4 is —CH 2 —;
R 11a is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, and —N(R 12b )C(═O)R 13c ;
R 12b is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and heterocyclo, (C 1 -C 4 alkoxy) C 1 -C 4 alkyl, and (hydroxy) C 1 -C 4 alkyl; and
R 13c is selected from the group consisting of alkyl, haloalkyl, alkoxy, (alkoxy) alkyl, (hydroxy) alkyl, (cyano) alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycle, amino, (amino) alkyl, (C 3 -C 6 cycloalkyl) oxy, and (4- to 8-membered heterocyclo) oxy;
R 1d is fluoro;
or a pharmaceutically acceptable salt or solvate thereof, and
(b) a Second Therapeutic Agent,
wherein:
the Second Therapeutic Agent is dexamethasone, pomalidomide, lenalidomide, venetoclax, CC-122, selinexor, panobinostat, or tazmetostat.
2 . The method of claim 1 , wherein the compound of Formula IV-A and the Second Therapeutic Agent are administered to the subject separately.
3 . The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt or solvate thereof.
4 . The method of claim 3 , wherein the compound and the second therapeutic agent are administered to the subject separately.
5 . The method of claim 3 , wherein the compound is:
or a pharmaceutically acceptable salt or solvate thereof.
6 . The method of claim 5 , wherein the Second Therapeutic Agent is dexamethasone.
7 . The method of claim 5 , wherein the Second Therapeutic Agent is pomalidomide or lenalidomide.
8 . The method of claim 5 , wherein the Second Therapeutic Agent is venetoclax.
9 . The method of claim 5 , wherein the Second Therapeutic Agent is CC-122.
10 . The method of claim 5 , wherein the Second Therapeutic Agent is selinexor.
11 . The method of claim 5 , wherein the Second Therapeutic Agent is panobinostat.
12 . The method of claim 5 , wherein the Second Therapeutic Agent is tazemetostat.
13 . The method of claim 5 , wherein the compound and the second therapeutic agent are administered to the subject separately.
14 . The method of claim 5 , wherein the cancer is multiple myeloma.
15 . The method of claim 14 , wherein the compound and the second therapeutic agent are administered to the subject separately.
16 . The method of claim 5 , wherein the cancer is mantle cell lymphoma.
17 . The method of claim 16 , wherein the compound and the second therapeutic agent are administered to the subject separately.
18 . The method of claim 16 , wherein the Second Therapeutic Agent is lenalidomide or venetoclax.
19 . The method of claim 18 , wherein the compound and the second therapeutic agent are administered to the subject separately.