Combination therapy for treating cancer
View Patent ↗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.
1. 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:
R 701 is H, F, OR 707 , NHR 707 , —(C≡C)—(CH 2 ) n7 -R 708 , phenyl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, C 1-3 alkyl, OH, O—C 1-6 alkyl, NH—C 1-6 alkyl, and, C 1-3 alkyl substituted with C 3-8 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the O—C 1-6 alkyl and NH—C 1-6 alkyl is optionally substituted with hydroxyl, O—C 1-3 alkyl or NH—C 1-3 alkyl, each of the O—C 1-3 alkyl and NH—C 1-3 alkyl being optionally further substituted with O—C 1-3 alkyl or NH—C 1-3 alkyl alkyl;
each of R 702 and R 703 , independently is H, halo, C 1-4 alkyl, C 1-6 alkoxyl or C 6 -C 10 aryloxy, each optionally substituted with one or more halo;
each of R 704 and R 705 , independently is C 1-4 alkyl;
R 706 is cyclohexyl substituted by N(C 1-4 alkyl) 2 wherein one or both of the C 1-4 alkyl is substituted with C 1-6 alkoxy; or R 706 is tetrahydropyranyl;
R 707 is C 1-4 alkyl optionally substituted with one or more groups selected from hydroxyl, C 1-4 alkoxy, amino, mono- or di-C 1-4 alkylamino, C 3-8 cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the C 3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with C 1-3 alkyl;
R 708 is C 1-4 alkyl optionally substituted with one or more groups selected from OH, halo, and C 1-4 alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or O—C 1-6 alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or C 1-6 alkyl; and
n7 is 0, 1 or 2.
2. The method of claim 1 , wherein the clear cell renal cell carcinoma is resistant to tyrosine kinase inhibitor treatment.
3. The method of claim 2 , wherein the one or more tyrosine kinase inhibitors are VEGF/VEGFR inhibitors.
4. 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:
R 701 is H, F, OR 707 , NHR 707 ,—(C≡C)—(CH 2 ) n7 -R 708 , phenyl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, C 1-3 alkyl, OH, O—C 1-6 alkyl, NH—C 1-6 alkyl, and, C 1-3 alkyl substituted with C 3-8 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the O—C 1-6 alkyl and NH—C 1-6 alkyl is optionally substituted with hydroxyl, O—C 1-3 alkyl or NH—C 1-3 alkyl, each of the O—C 1-3 alkyl and NH—C 1-3 alkyl being optionally further substituted with O—C 1-3 alkyl or NH—C 1-3 alkyl;
each of R 702 and R 703 , independently is H, halo, C 1-4 alkyl, C 1-6 alkoxyl or C 6 -C 10 aryloxy, each optionally substituted with one or more halo;
each of R 704 and R 705 , independently is C 1-4 alkyl;
R 706 is cyclohexyl substituted by N(C 1-4 alkyl) 2 wherein one or both of the C 1-4 alkyl is substituted with C 1-6 alkoxy; or R 706 is tetrahydropyranyl;
R 707 is C 1-4 alkyl optionally substituted with one or more groups selected from hydroxyl, C 1-4 alkoxy, amino, mono- or di-C 1-4 alkylamino, C 3-8 cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the C 3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with C 1-3 alkyl;
R 708 is C 1-4 alkyl optionally substituted with one or more groups selected from OH, halo, and C 1-4 alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or O—C 1-6 alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or C 1-6 alkyl; and
n7 is 0, 1 or 2.
5. The method of claim 4 , wherein the renal cell carcinoma is resistant to VEGF/VEGFR inhibitor treatment.
6. The method of claim 1 , wherein the EZH2 inhibitor is Compound 44 having the following formula:
or pharmaceutically acceptable salt thereof.
7. The method of claim 1 , wherein the EZH2 inhibitor is:
or pharmaceutically acceptable salt thereof.
8. The method of claim 1 , wherein the EZH2 inhibitor is GSK-126.
9. The method of claim 1 , wherein the one or more tyrosine kinase inhibitors are selected from erlotinib (Tarceva); gefitinib (Iressa); imatinib (Gleevec); sorafenib (Nexavar); sunitinib (Sutent); trastuzumab (Herceptin); bevacizumab (Avastin); rituximab (Rituxan); lapatinib (Tykerb); cetuximab (Erbitux); panitumumab (Vectibix); everolimus (Afinitor); alemtuzumab (Campath); gemtuzumab (Mylotarg); temsirolimus (Torisel); pazopanib (Votrient); dasatinib (Sprycel); nilotinib (Tasigna); vatalanib (Ptk787; ZK222584); CEP-701; SU5614; MLN518; XL999; VX-322; Azd0530; BMS-354825; SKI-606 CP-690; AG-490; WHI-P154; WHI-P131; AC-220; and AMG888.
10. The method of claim 1 , wherein the one or more tyrosine kinase inhibitors include sunitinib.
11. The method of claim 4 , wherein the one or more VEGF/VEGFR inhibitors are selected from bevacizumab (Avastin); sorafenib (Nexavar);
sunitinib (Sutent); ranibizumab; pegaptanib; vandetinib; E7080; Zd6474; PKC-412; Vatalanib (Ptk787 or ZK222584); and motesanib diphosphate.
12. The method of claim 4 , wherein the one or more VEGF/VEGFR inhibitors include sunitinib.
13. The method of claim 1 , wherein the EZH2 inhibitor and the one or more tyrosine kinase inhibitors are administered simultaneously or sequentially.
14. The method of claim 1 , wherein the EZH2 inhibitor is administered prior to administration of the one or more tyrosine kinase inhibitors.
15. The method of claim 4 , wherein the EZH2 inhibitor and the one or more VEGF/VEGFR inhibitors are administered simultaneously or sequentially.
16. The method of claim 4 , wherein the EZH2 inhibitor is administered prior to administration of the one or more VEGF/VEGFR inhibitors.
17. The method of claim 4 , wherein the renal cell carcinoma is clear cell renal cell carcinoma.
18. The method of claim 4 , wherein the EZH2 inhibitor is Compound 44 having the following formula:
or pharmaceutically acceptable salt thereof.
19. The method of claim 4 , wherein the EZH2 inhibitor is:
or pharmaceutically acceptable salt thereof.
20. The method of claim 4 , wherein the EZH2 inhibitor is GSK-126.