Publication details
Novel modulators of cell cycle checkpoints and their use in combination with checkpoint kinase inhibitors
| Authors | |
|---|---|
| Year of publication | 2009 |
| Type | Patent |
| MU Faculty or unit | |
| Publisher | World Intellectual Property Organization |
| State | United States |
| Patent's number | WO 2009/061781 A1 |
| Description | Pyrimidine nucleoside analogs I were prepd., wherein G is H, halo, alkyl; X and Y are independently H, F, OR2, alkyl;Z is O, NR2, S, CR2R3, SO2; R is alkyl, alkenyl, cycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, alkylheterocyclyl, alkyl-C(O)R2 and alkyl-C(O)NR2R3, wherein each of said alkyl, aryl, heteroaryl and heterocyclyl can be (un)substituted with one or more groups which can be the same or different, each substituent being independently selected from the group consisting of halo, cyano, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, OR, NR2R3, C(O)R2, C(O)OR2 and C(O)NR2R3; R2 is H, alkyl, aryl, heteroaryl, wherein each of said alkyl, aryl and heteroaryl can be unsubstituted or optionally independently substituted with one or more groups which can be the same or different and are independently selected from the group consisting of halo, cyano, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, aryl, heterocyclyl, cycloalkyl, cycloalkenyl -OR2, NR2R3, C(O)R2, C(O)NR2R3; R3 is alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, OR2, NR2R3, C(O)R2 and C(O)NR2R3 as targeted mechanism-based modulators of cell cycle checkpoints. Cancers and/or malignancies can be treated by administration of a cell cycle checkpoint modulator of the invention. Also discussed are suitable combinations of the cell cycle checkpoint modulator with a checkpoint kinase inhibitor to produce synergistic apoptosis in cancer cells. The invention includes methods of treating cancers by administering the combination of the cell cycle checkpoint modulator and the checkpoint kinase inhibitor, pharmaceutical compns. comprising the activator as well as the combination and pharmaceutical kits. Thus, nucleosides II was prepd. and tested as kinase inhibitor and anticancer agent, wherein the cancer is selected from the group consisting of: cancer of the bladder, breast, colon, kidney, liver, lung, small cell lung cancer, non-small cell lung cancer, head and neck esophagus, gall bladder, ovary, cervix thyroid, prostate, and skin, squamous cell carcinoma; leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell Iymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, and Burketlt's lymphoma; acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma and melanoma, teratocarcinoma, osteosarcoma, thyroid cancer and Kaposi's sarcoma. |