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Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors

文献类型：期刊论文

作者Lin, Tingting1,2,3,4,5; Li, Jiacheng3,5; Liu, Liping3,5; Li, Yuanqing3,5; Jiang, Hualiang1,2,3,5; Chen, Kaixian1,2,3,5; Xu, Pan3; Luo, Cheng1,2,3,5; Zhou, Bing4,5
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-04-05
卷号215页码:12
关键词CDK2 inhibitor Selectivity Anti-proliferative potency
ISSN号0223-5234
DOI10.1016/j.ejmech.2021.113281
通讯作者Xu, Pan(xupan_322@simm.ac.cn) ; Luo, Cheng() ; Zhou, Bing(zhoubing@simm.ac.cn)
英文摘要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. (c) 2021 Elsevier Masson SAS. All rights reserved.
资助项目National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81821005] ; K. C. Wong Education ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program[2018ZX09711002-008]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000634820600026
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/295229]  
专题新药研究国家重点实验室
通讯作者Xu, Pan; Luo, Cheng; Zhou, Bing
作者单位1.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 200031, Peoples R China
2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Ctr Chem Biol,Drug Discovery & Design Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Lin, Tingting,Li, Jiacheng,Liu, Liping,et al. Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2021,215:12.
APA Lin, Tingting.,Li, Jiacheng.,Liu, Liping.,Li, Yuanqing.,Jiang, Hualiang.,...&Zhou, Bing.(2021).Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,215,12.
MLA Lin, Tingting,et al."Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 215(2021):12.

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来源：上海药物研究所

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