化学
细胞周期蛋白依赖激酶2
细胞周期蛋白依赖激酶
吡唑
细胞周期蛋白依赖激酶1
细胞培养
细胞生长
激酶
细胞周期
癌症研究
CDK抑制剂
立体化学
药理学
细胞凋亡
生物化学
生物
遗传学
作者
Tingting Lin,Jiacheng Li,Liping Liu,Yuanqing Li,Hualiang Jiang,Kaixian Chen,Pan Xu,Cheng Luo,Bing Zhou
标识
DOI:10.1016/j.ejmech.2021.113281
摘要
Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
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