Design, synthesis, and molecular docking study of 3H-imidazole[4,5-c]pyridine derivatives as CDK2 inhibitors

被引：7

作者：

Wu, Yi-Zhe ^{[1
]}

Ying, Hua-Zhou ^{[1
]}

Xu, Lei ^{[2
,3
]}

Cheng, Gang ^{[4
]}

Chen, Jing ^{[4
]}

Hu, Yong-Zhou ^{[1
]}

Liu, Tao ^{[1
]}

Dong, Xiao-Wu ^{[1
]}

机构：

[1] Zhejiang Univ, ZJU ENS Joint Lab Med Chem, Zhejiang Prov Key Lab Anticanc Drug Res, Coll Pharmaceut Sci,Hangzhou Inst Innovat Med, Hangzhou 310058, Zhejiang, Peoples R China

[2] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China

[3] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China

[4] Zhejiang Chinese Med Univ, Coll Pharmaceut Sci, Hangzhou 311402, Zhejiang, Peoples R China

来源：

ARCHIV DER PHARMAZIE | 2018年 / 351卷 / 06期

基金：

中国国家自然科学基金;

关键词：

cancer; CDK2; inhibitor; imidazo[4; 5-c]pyridine; targeted therapy; CYCLIN-DEPENDENT KINASES; CELL-CYCLE; CANCER-THERAPY; POTENT; DISCOVERY; TARGETS; AGENTS;

D O I：

10.1002/ardp.201700381

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of imidazo[4,5-c]pyridine-based CDK2 inhibitors were designed from the structure of CYC202 via scaffold hopping strategy. These compounds were synthesized and biologically evaluated for their CDK2 inhibitory and in vitro anti-proliferation potential against cancer cell lines. Several compounds exhibited potent CDK2 inhibition with IC50 values of less than 1 mu M. The most potent compound 5b showed excellent CDK2 inhibitory (IC50=21nM) and in vitro anti-proliferation activity against three different cell lines (HL60, A549, and HCT116). The molecular docking and dynamic studies portrayed the potential binding mechanism between 5b and CDK2, and several key interactions between them were observed, which would be the reason for its potent CDK2 inhibitory and anti-proliferation activities. Therefore, the pyridin-3-ylmethyl moiety would serve as an excellent pharmacophore for the development of novel CDK2 inhibitors for targeted anti-cancer therapy.

引用

页数：8

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