| Přispěvatelé: |
Fanta, Biruk Sintayehu, Mekonnen, Laychiluh, Basnet, Sunita KC, Teo, Theodosia, Lenjisa, Jimma, Khair, Nishat Z, Kou, Lianmeng, Tadesse, Solomon, Sykes, Matthew J, Yu, Mingfeng, Wang, Shudong |
| Popis: |
Refereed/Peer-reviewed Deregulation of cyclin-dependent kinase 2 (CDK2) and its activating partners, cyclins A and E, is associated with the pathogenesis of a myriad of human cancers and with resistance to anticancer drugs including CDK4/6 inhibitors. Thus, CDK2 has become an attractive target for the development of new anticancer therapies and for the amelioration of the resistance to CDK4/6 inhibitors. Bioisosteric replacement of the thiazole moiety of CDKI-73, a clinically trialled CDK inhibitor, by a pyrazole group afforded 9 and 19 that displayed potent CDK2-cyclin E inhibition (Ki = 0.023 and 0.001 μM, respectively) with submicromolar antiproliferative activity against a panel of cancer cell lines (GI50 = 0.025–0.780 μM). Mechanistic studies on 19 with HCT-116 colorectal cancer cells revealed that the compound reduced the phosphorylation of retinoblastoma at Ser807/811, arrested the cells at the G2/M phase, and induced apoptosis. These results highlight the potential of the 2-anilino-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine series in developing potent and selective CDK2 inhibitors to combat cancer. |
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