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Design, Synthesis, and Biological Evaluation of 2,4-Diaminopyrimidine Derivatives as Potent CDK7 Inhibitors

文献类型：期刊论文

作者Zhang, Hualin10,11; Tu, Yutong7,8,9; Tao, Zhaofan7,11; Gao, Lixin8; Huang, Shengjie6; Gao, Mingshan11; Mao, Jialuo5,8,9; Zhou, Yang6; Li, Yupeng3,4; Li, Jia2,7,9
刊名ACS MEDICINAL CHEMISTRY LETTERS
出版日期2024-07-16
页码8
关键词CDK7 inhibitor 2,4-diaminopyrimidine selectivity anticancer
ISSN号1948-5875
DOI10.1021/acsmedchemlett.4c00040
通讯作者Li, Jia(jli@simm.ac.cn) ; Zhou, Yubo(ybzhou@simm.ac.cn) ; Xu, Tianfeng(tfxu@simm.ac.cn)
英文摘要Developing selective CDK7 inhibitors has emerged as a promising approach for cancer treatment owing to the critical role of CDK7 in cancer progression. Starting from BTX-A51, a CK1 alpha inhibitor that also targets CDK7 and CDK9, we designed and synthesized a series of 2,4-diaminopyrimidine derivatives as potent CDK7 inhibitors. The representative compound, 22, displayed significant enzymatic inhibitory activity and demonstrated a remarkable selectivity profile against a panel of kinases, including seven CDK subtypes. Modeling studies and molecular dynamics simulations revealed that the sulfone group of 22 significantly enhanced the binding affinity, while the acetyl group contributed to the increased selectivity of CDK7 against CDK9. Compound 22 effectively inhibited the phosphorylation of RNA polymerase II and CDK2 and resulted in G1/S phase cell cycle arrest and apoptosis in MV4-11 cells. It appears to be a promising lead compound for the development of a CDK7 inhibitor for cancer therapy.
WOS关键词KINASE ; PHOSPHORYLATION ; ACTIVATION ; RECEPTOR ; TFIIH
资助项目National Natural Science Foundation of China[22107110] ; Guangdong High-level New RD Institute[2023000003] ; Guangdong High-level New RD Institute[2019B090904008] ; Guangdong High-level Innovative Research Institute[2021B0909050003]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001270017300001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/312407]  
专题中国科学院上海药物研究所
通讯作者Li, Jia; Zhou, Yubo; Xu, Tianfeng
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
3.Univ Texas EI Paso, Border Biomed Res Ctr, EI Paso, TX 79902 USA
4.Univ Texas EI Paso, Sch Pharm, Dept Pharmaceut Sci, EI Paso, TX 79902 USA
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
6.Jinan Univ, Int Cooperat Lab Tradit Chinese Med Modernizat & I, Guangzhou City Key Lab Precis Chem Drug Dev, Sch Pharm,Chinese Minist Educ,State Key Lab Bioact, Guangzhou 510632, Peoples R China
7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
8.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
9.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
10.Shanghai Univ, Coll Sci, Dept Chem, Shanghai 200444, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Hualin,Tu, Yutong,Tao, Zhaofan,et al. Design, Synthesis, and Biological Evaluation of 2,4-Diaminopyrimidine Derivatives as Potent CDK7 Inhibitors[J]. ACS MEDICINAL CHEMISTRY LETTERS,2024:8.
APA Zhang, Hualin.,Tu, Yutong.,Tao, Zhaofan.,Gao, Lixin.,Huang, Shengjie.,...&Xu, Tianfeng.(2024).Design, Synthesis, and Biological Evaluation of 2,4-Diaminopyrimidine Derivatives as Potent CDK7 Inhibitors.ACS MEDICINAL CHEMISTRY LETTERS,8.
MLA Zhang, Hualin,et al."Design, Synthesis, and Biological Evaluation of 2,4-Diaminopyrimidine Derivatives as Potent CDK7 Inhibitors".ACS MEDICINAL CHEMISTRY LETTERS (2024):8.

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来源：上海药物研究所

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