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Discovery of novel 2,4-diarylaminopyrimidine derivatives as potent and selective epidermal growth factor receptor (EGFR) inhibitors against L858R/T790M resistance mutation

文献类型：期刊论文

作者Yan, Qi2; Chen, Yuzhe3,4; Tang, Baiyou1,3; Xiao, Qiang2; Qu, Rong3,4; Tong, Linjiang3; Liu, Jian2; Ding, Jian3; Chen, Yi3; Ding, Ning2
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2018-05-25
卷号152页码:298-306
关键词EGFR inhibitors Pyrimidine derivatives Mutant selective inhibitors AZD9291 T790M
ISSN号0223-5234
DOI10.1016/j.ejmech.2018.04.052
文献子类Article
英文摘要A series of novel 2,4-diarylaminopyrimidine derivatives of AZD9291 were discovered as L858R/T790M mutant selective epidermal growth factor receptor (EGFR) inhibitors. The majority of these compounds exhibited moderate to excellent EGFR 1790 M/L858R inhibitory activities and comparable anti proliferative activities against double mutant over-expressed NCI-H1975 cells to that of AZD9291. The most promising compounds 8a displayed an IC50 of 4.1 nM against EGFR L858R/T790M mutants. 8a also showed excellent cytotoxic effect against NCI-H1975 cells with an IC50 of 59 nM and 100-fold selectivity over wide-type EGFR over-expressed A431 cells. Compound 8a significantly inhibited tumor growth in NCI-H1975 xenograft models at a non-toxic dose. Docking study performed for 8a with ATP binding site of EGFR-TK showed the similar binding mode to that of AZD9291. All these results suggested that compound 8a was a potential mutant-selective EGFR inhibitor. (C) 2018 Elsevier Masson SAS. All rights reserved.
WOS关键词CELL LUNG-CANCER ; IN-VITRO ; AFATINIB ; AZD9291
资助项目Shanghai Science and Technology Innovation Fund[17431902400] ; Chinese Academy of Sciences[XDA12020209]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000435048900024
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/279744]  
专题药理学第一研究室
中科院受体结构与功能重点实验室
新药研究国家重点实验室
通讯作者Tan, Wenfu; Xie, Hua; Li, Yingxia
作者单位1.Cent S Univ, Xiangya Hosp, Dept Clin Pharmacol, Changsha 410008, Hunan, Peoples R China
2.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China;
推荐引用方式
GB/T 7714		 Yan, Qi,Chen, Yuzhe,Tang, Baiyou,et al. Discovery of novel 2,4-diarylaminopyrimidine derivatives as potent and selective epidermal growth factor receptor (EGFR) inhibitors against L858R/T790M resistance mutation[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,152:298-306.
APA Yan, Qi.,Chen, Yuzhe.,Tang, Baiyou.,Xiao, Qiang.,Qu, Rong.,...&Li, Yingxia.(2018).Discovery of novel 2,4-diarylaminopyrimidine derivatives as potent and selective epidermal growth factor receptor (EGFR) inhibitors against L858R/T790M resistance mutation.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,152,298-306.
MLA Yan, Qi,et al."Discovery of novel 2,4-diarylaminopyrimidine derivatives as potent and selective epidermal growth factor receptor (EGFR) inhibitors against L858R/T790M resistance mutation".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 152(2018):298-306.

入库方式： OAI收割

来源：上海药物研究所

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