Combination therapy for treating cancer
AssigneesEpizyme, Inc., Health Research, Inc.
InventorsHeike Keilhack, Roberto Pili
Life of this patent
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Abstract
The present disclosure relates to compositions comprising inhibitors of human histone methyltransferase EZH2 and one or more other therapeutic agents (such as tyrosine kinase inhibitors or VEGF/VEGFR inhibitors), particularly anticancer agents such as sunitinib, and methods of combination therapy for administering to subjects in need thereof for the treatment of cancer.
Claims20
A method for treating clear cell renal cell carcinoma in a patient in need thereof comprising administering a therapeutically effective amount of an EZH2 inhibitor and one or more tyrosine kinase inhibitors, wherein the EZH2 inhibitor is GSK-126 having the following formula:
- or a pharmaceutically acceptable salt thereof;
- or
- a compound of Formula (I):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- R701 is H, F, OR707, NHR707, —(C≡C)—(CH2)n7-R708, phenyl, 5- or 6-membered heteroaryl, C3-8 cycloalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, 5- or 6-membered heteroaryl, C3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, C1-3 alkyl, OH, O—C1-6 alkyl, NH—C1-6 alkyl, and, C1-3 alkyl substituted with C3-8 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the O—C1-6 alkyl and NH—C1-6 alkyl is optionally substituted with hydroxyl, O—C1-3 alkyl or NH—C1-3 alkyl, each of the O—C1-3 alkyl and NH—C1-3 alkyl being optionally further substituted with O—C1-3 alkyl or NH—C1-3 alkyl alkyl;
- each of R702 and R703, independently is H, halo, C1-4 alkyl, C1-6 alkoxyl or C6-C10 aryloxy, each optionally substituted with one or more halo;
- each of R704 and R705, independently is C1-4 alkyl;
- R706 is cyclohexyl substituted by N(C1-4 alkyl)2 wherein one or both of the C1-4 alkyl is substituted with C1-6 alkoxy;
- or R706 is tetrahydropyranyl;
- R707 is C1-4 alkyl optionally substituted with one or more groups selected from hydroxyl, C1-4 alkoxy, amino, mono- or di-C1-4 alkylamino, C3-8 cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the C3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with C1-3 alkyl;
- R708 is C1-4 alkyl optionally substituted with one or more groups selected from OH, halo, and C1-4 alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or O—C1-6 alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or C1-6 alkyl;
- and
- n7 is 0, 1 or 2.
A method for treating renal cell carcinoma in a patient in need thereof comprising administering a therapeutically effective amount of an EZH2 inhibitor and one or more VEGF/VEGFR inhibitors, wherein the EZH2 inhibitor is GSK-126 having the following formula:
- or a pharmaceutically acceptable salt thereof;
- or
- a compound of Formula (I):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- R701 is H, F, OR707, NHR707,—(C≡C)—(CH2)n7-R708, phenyl, 5- or 6-membered heteroaryl, C3-8 cycloalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, 5- or 6-membered heteroaryl, C3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, C1-3 alkyl, OH, O—C1-6 alkyl, NH—C1-6 alkyl, and, C1-3 alkyl substituted with C3-8 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the O—C1-6 alkyl and NH—C1-6 alkyl is optionally substituted with hydroxyl, O—C1-3 alkyl or NH—C1-3 alkyl, each of the O—C1-3 alkyl and NH—C1-3 alkyl being optionally further substituted with O—C1-3 alkyl or NH—C1-3 alkyl;
- each of R702 and R703, independently is H, halo, C1-4 alkyl, C1-6 alkoxyl or C6-C10 aryloxy, each optionally substituted with one or more halo;
- each of R704 and R705, independently is C1-4 alkyl;
- R706 is cyclohexyl substituted by N(C1-4 alkyl)2 wherein one or both of the C1-4 alkyl is substituted with C1-6 alkoxy;
- or R706 is tetrahydropyranyl;
- R707 is C1-4 alkyl optionally substituted with one or more groups selected from hydroxyl, C1-4 alkoxy, amino, mono- or di-C1-4 alkylamino, C3-8 cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the C3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with C1-3 alkyl;
- R708 is C1-4 alkyl optionally substituted with one or more groups selected from OH, halo, and C1-4 alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or O—C1-6 alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or C1-6 alkyl;
- and
- n7 is 0, 1 or 2.
Dependencies are inferred from the claim text.