EIF4A INHIBITOR COMBINATIONS
The present disclosure relates to methods for ameliorating or treating an eIF4A dependent condition or disease in a subject in need thereof. The methods of the disclosure comprise administering to the subject a therapeutically effective amount of at least one eukaryotic translation initiation factor 4A (eIF4A) inhibitor and a therapeutically effective amount of at least one cyclin-dependent kinase (CDK) inhibitor.
1 . A method for ameliorating or treating an eIF4A dependent condition in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one eukaryotic translation initiation factor 4A (eIF4A) inhibitor and a therapeutically effective amount of at least one cyclin-dependent kinase (CDK) inhibitor, wherein the at least one eIF4A inhibitor comprises a compound in accordance with Formula I:
or stereoisomers, tautomers or pharmaceutically acceptable salts thereof,
wherein:
X is CR 6 R 7 , O, S, NH, N(C 1 -C 8 )alkyl, C(O), C═CR 6 R 7 , N(CO)R 8 , S(O) or S(O) 2 ;
Y is a 5-membered heteroaryl or a 6-membered aryl or heteroaryl;
R 1 and R 2 independently are aryl, heterocyclyl, heteroaryl or cycloalkyl;
R 3a , R 3b , R 4a and R 4b independently are H, halogen, CN, C 1 -C 8 (alkyl), (C 1 -C 8 )haloalkyl, C 2 -C 8 (alkenyl), (C 2 -C 8 )alkynyl, OR 9 , NHR 9 , NR 9 R 9 , [(C 1 -C 8 )alkylene]OR 9 , [(C 1 -C 8 )alkylene]NHR 9 , [(C 1 -C 8 )alkylene]NR 9 R 9 , C(O)R 8 , C(O)NHR 9 , C(O)NR 9 R 9 , C(O)[(C 1 -C 8 )alkylene]NHR 9 , C(O)[(C 1 -C 8 )alkylene]NR 9 R 9 , CO 2 R 9 , C(S)NHR 9 , C(S)NR 9 R 9 , SR 9 , S(O)R 9 , SO 2 R 9 , SO 2 NHR 9 , SO 2 NR 9 R 9 , NH(CO)R 8 , NR 9 (CO)R 8 , NH(CO)NHR 9 , NH(CO)NR 9 R 9 , NR 9 (CO)NHR 9 , NR 9 (CO)NR 9 R 9 , P(O)(OH)(OR 9 ), P(O)(OR 9 )(OR 9 ), aryl, heteroaryl, cycloalkyl or heterocyclyl;
R 3a and R 3b , and R 4a and R 4b independently combine to form oxo or alkenyl, or a cycloalkyl or heterocyclyl ring; or
R 3a and R 4a , R 3b and R 4b or R 4a and R 5 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring; or
R 2 and R 3a together with the carbon atom to which they are attached form a bicyclic ring system;
R 5 is H, halogen, OH, CN, N 3 , SR 9 , (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, O(C 1 -C 8 )alkyl, O(C 1 -C 8 )haloalkyl, (C 2 -C 8 )alkynyl, NHC(O)(C 1 -C 8 )alkyl or heteroaryl;
R 6 and R 7 independently are H, CN, halogen, OR 9 , SR 9 , (C 1 -C 8 )alkyl, NH(R 9 ) or NR 9 R 9 ;
R 8 is H, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, O(C 1 -C 8 )alkyl, O(C 1 -C 8 )haloalkyl, cycloalkyl, O(cycloalkyl), heterocyclyl, O(heterocyclyl), aryl, O(aryl), heteroaryl or O(heteroaryl);
R 9 is H, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, cycloalkyl, heterocyclyl, [(C 1 -C 8 )alkylene] heterocyclyl, aryl, [(C 1 -C 8 )alkylene] aryl or heteroaryl;
wherein the two R 9 's together with the nitrogen atom to which they are attached of NR 9 R 9 , [(C 1 -C 8 )alkylene]NR 9 R 9 , C(O)NR 9 R 9 , C(O)[(C 1 -C 8 )alkylene]NR 9 R 9 , C(S)NR 9 R 9 , SO 2 NR 9 R 9 , NH(CO)NR 9 R 9 or NR 9 (CO)NR 9 R 9 , optionally form a heterocyclyl ring;
wherein any alkyl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2, or 3 groups selected from OH, CN, SH, SO 2 NH 2 , SO 2 (C 1 -C 4 )alkyl, SO 2 NH(C 1 -C 4 )alkyl, halogen, NH 2 , NH(C 1 -C 4 )alkyl, N[(C 1 -C 4 )alkyl] 2 , C(O)NH 2 , COOH, COOMe, acetyl, (C 1 -C 8 )alkyl, O(C 1 -C 8 )alkyl, O(C 1 -C 8 )haloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, NH 2 —C(O)-alkylene, NH(Me)-C(O)-alkylene, CH 2 —C(O)-lower alkyl, C(O)-lower alkyl, alkylcarbonylaminyl, CH 2 —[CH(OH)] m —(CH 2 ) p —OH, CH 2 —[CH(OH)] m —(CH 2 ) p —NH 2 or CH 2 -aryl-alkoxy; or
wherein any alkyl, cycloalkyl or heterocyclyl is optionally substituted with oxo;
“m” and “p” are 1, 2, 3, 4, 5 or 6; and
wherein when Y is a 6-membered aryl then X is not O.
2 . The method according to claim 1 , wherein the at least one CDK inhibitor is a CDK4/6 inhibitor.
3 . The method according to claim 2 , wherein the CDK4/6 inhibitor is selected from the group consisting of palbociclib, ribociclib, abemaciclib, trilaciclib, flavopiridol (alvocidib), G1T28-1, G1T38, ON123300, AT7519HCl, P276-00, AT7519, JNJ-7706621, SHR6390, PF-06873600, and derivatives thereof.
4 . The method according to claim 3 , wherein the CDK4/6 inhibitor is palbociclib, ribociclib, or abemaciclib.
5 . The method according to claim 1 , wherein the at least one eIF4A inhibitor is a compound according to the following formula:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
6 . The method according to claim 1 , wherein the at least one eIF4A inhibitor and/or the at least one CDK inhibitor is administered to the subject via a route selected from the group consisting of orally, intravenously, intramuscularly, transarterially, intraperitoneally, intranasally, subcutaneously, endoscopically, transdermally, or intrathecally.
7 . The method according to claim 1 , wherein the at least one eIF4A inhibitor is administered to the subject in the range from about 0.01 mg/Kg to about 100 mg/Kg.
8 . The method according to claim 7 , wherein the at least one eIF4A inhibitor is administered to the subject intravenously at about 0.1 mg/Kg, every 4 days, for about 25 days.
9 . The method according to claim 1 , wherein the at least one CDK inhibitor is administered to the subject in the range from about 0.01 mg/Kg to about 100 mg/Kg.
10 . The method according to claim 9 , wherein the at least one CDK inhibitor is administered to the subject orally at about 30 mg/Kg, every day, for about 25 days.
12 . The method according to claim 1 , wherein the eIF4A dependent condition is a disease of uncontrolled cell growth, proliferation and/or survival.
13 . The method according to claim 12 , wherein the eIF4A dependent condition is cancer.
14 . The method of claim 13 , wherein the cancer is selected from the group consisting of solid tumor, colorectal cancer, bladder cancer, gastric cancer, thyroid cancer, esophageal cancer, head and neck cancer, brain cancer, malignant glioma, fibrotic diseases, glioblastoma, hepatocellular cancers, thyroid cancer, lung cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, melanoma, multiple melanoma, myeloma, pancreatic cancer, pancreatic carcinoma, renal cell carcinoma, renal cancer, cervical cancer, urothelial cancer, prostate cancer, castration-resistant prostate cancer, ovarian cancer, breast cancer, triple-negative breast cancer, leukemia, acute myeloid leukemia, Hodgkins lymphoma, non-Hodgkins lymphoma, mantle cell lymphoma, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, multiple myeloma, and liposarcoma.
15 . The method of claim 14 , wherein the cancer is breast cancer.
16 . The method of claim 15 , wherein the breast cancer is estrogen receptor-positive (ER + ) breast cancer.
17 . The method of claim 14 , wherein the cancer is non-small cell lung cancer (NSCLC).
18 . The method of claim 17 , wherein the non-small cell lung cancer (NSCLC) is Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant NSCLC.
19 . The method of claim 14 , wherein the cancer is colorectal cancer.
20 . A method for ameliorating or treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an eIF4A inhibitor and a therapeutically effective amount of a CDK4/6 inhibitor, wherein the eIF4A inhibitor is a compound according to the following formula:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and wherein the CDK4/6 inhibitor is selected from the group consisting of palbociclib, ribociclib, and abemaciclib.