细胞周期蛋白依赖激酶2
化学
细胞周期蛋白依赖激酶
部分
吡唑
激酶
胺气处理
立体化学
细胞凋亡
组合化学
细胞周期
生物化学
有机化学
作者
Biruk Sintayehu Fanta,Jimma Likisa Lenjisa,Theodosia Teo,Lianmeng Kou,Laychiluh Bantie,Yuchao Yang,Sunita K. C. Basnet,Ramin Hassankhani,Matthew J. Sykes,Mingfeng Yu,Shudong Wang
出处
期刊:Molecules
[MDPI AG]
日期:2023-03-25
卷期号:28 (7): 2951-2951
被引量:2
标识
DOI:10.3390/molecules28072951
摘要
Cyclin-dependent kinase 2 (CDK2) has been garnering considerable interest as a target to develop new cancer treatments and to ameliorate resistance to CDK4/6 inhibitors. However, a selective CDK2 inhibitor has yet to be clinically approved. With the desire to discover novel, potent, and selective CDK2 inhibitors, the phenylsulfonamide moiety of our previous lead compound 1 was bioisosterically replaced with pyrazole derivatives, affording a novel series of N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amines that exhibited potent CDK2 inhibitory activity. Among them, 15 was the most potent CDK2 inhibitor (Ki = 0.005 µM) with a degree of selectivity over other CDKs tested. Meanwhile, this compound displayed sub-micromolar antiproliferative activity against a panel of 13 cancer cell lines (GI50 = 0.127-0.560 μM). Mechanistic studies in ovarian cancer cells revealed that 15 reduced the phosphorylation of retinoblastoma at Thr821, arrested cells at the S and G2/M phases, and induced apoptosis. These results accentuate the potential of the N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amine scaffold to be developed into potent and selective CDK2 inhibitors for the treatment of cancer.
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