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

被引：0

作者：

Zhang, Hualin ^{[1
,2
]}

Tu, Yutong ^{[3
,4
,5
]}

Tao, Zhaofan ^{[1
,5
]}

Gao, Lixin ^{[4
]}

Huang, Shengjie ^{[6
]}

Gao, Mingshan ^{[1
]}

Mao, Jialuo ^{[3
,4
,7
]}

Zhou, Yang ^{[6
]}

Li, Yupeng ^{[8
,9
]}

Li, Jia ^{[3
,5
,10
]}

Zhou, Yubo ^{[3
,4
,5
,7
]}

Xu, Tianfeng ^{[1
,5
,11
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China

[2] Shanghai Univ, Coll Sci, Dept Chem, Shanghai 200444, Peoples R China

[3] Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China

[4] Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

[5] Univ Chinese Acad Sci, Beijing 100049, 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] Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China

[8] Univ Texas EI Paso, Sch Pharm, Dept Pharmaceut Sci, EI Paso, TX 79902 USA

[9] Univ Texas EI Paso, Border Biomed Res Ctr, EI Paso, TX 79902 USA

[10] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China

[11] Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2024年 / 15卷 / 08期

基金：

中国国家自然科学基金;

关键词：

CDK7; inhibitor; 2,4-diaminopyrimidine; selectivity; anticancer; KINASE; PHOSPHORYLATION; ACTIVATION; RECEPTOR; TFIIH;

D O I：

10.1021/acsmedchemlett.4c00040

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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.

引用

页码：1213 / 1220

页数：8

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