Structure-based design and synthesis of 2,4-diaminopyrimidines as EGFR L858R/T790M selective inhibitors for NSCLC

doi:10.1016/j.ejmech.2017.08.061

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	Structure-based design and synthesis of 2,4-diaminopyrimidines as EGFR L858R/T790M selective inhibitors for NSCLC
	Chen, Lingfeng 2,3; Fu, Weitao 3; Feng, Chen 3; Qu, Rong 1; Tong, Linjiang 1; Zheng, Lulu 3; Fang, Bo 3; Qiu, Yinda 3; Hu, Jie 3; Cai, Yuepiao 3
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2017-11-10
卷号	140 页码:510-527
关键词	Epidermal growth factor receptor Tyrosine kinase inhibitors Non-small cell lung cancer T790M Mutant-selective
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2017.08.061
文献子类	Article
英文摘要	Mutated epidermal growth factor receptor (EGFR) is a major driver of non-small cell lung cancer (NSCLC). The EGFR(T790m) secondary mutation has become a leading cause of clinically-acquired resistance to gefitinib and erlotinib. Herein, we present a structure-based design approach to increase the potency and selectivity of the previously reported reversible EGFR inhibitor 7, at the kinase and cellular levels. Three step structure-activity relationship exploration led to promising compounds 19e and 19h with unique chemical structure and binding mode from the other third-generation tyrosine kinase inhibitors. In a human NSCLC xenograft model, 19e and 19h exhibited dose-dependent tumor growth suppression without toxicity. These selective inhibitors are promising drug candidates for EGFR(T790M)-driven NSCLC. (C) 2017 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Funding of China[81502912] ; National Natural Science Funding of China[21472142] ; National Natural Science Funding of China[81622043] ; Natural Science Funding of Zhejiang Province[LY17B020008] ; Natural Science Funding of Zhejiang Province[LY17H300004] ; Natural Science Funding of Zhejiang Province[LQ15H300002]
WOS关键词	GROWTH-FACTOR RECEPTOR ; CELL LUNG-CANCER ; TYROSINE KINASE INHIBITOR ; T790M-MEDIATED RESISTANCE ; IRREVERSIBLE INHIBITOR ; COVALENT INHIBITORS ; MUTANT ; T790M ; DISCOVERY ; MUTATION
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000414620000036
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272407]
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	Ding, Jian; Liu, Zhiguo; Liang, Guang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Nanjing Univ Sci & Technol, Sch Chem Engn, Nanjing 210094, Jiangsu, Peoples R China; 3.Wenzhou Med Univ, Sch Pharmaceut Sci, Chem Biol Res Ctr, Wenzhou 325035, Zhejiang, Peoples R China;
推荐引用方式 GB/T 7714	Chen, Lingfeng,Fu, Weitao,Feng, Chen,et al. Structure-based design and synthesis of 2,4-diaminopyrimidines as EGFR L858R/T790M selective inhibitors for NSCLC[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2017,140:510-527.
APA	Chen, Lingfeng.,Fu, Weitao.,Feng, Chen.,Qu, Rong.,Tong, Linjiang.,...&Liang, Guang.(2017).Structure-based design and synthesis of 2,4-diaminopyrimidines as EGFR L858R/T790M selective inhibitors for NSCLC.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,140,510-527.
MLA	Chen, Lingfeng,et al."Structure-based design and synthesis of 2,4-diaminopyrimidines as EGFR L858R/T790M selective inhibitors for NSCLC".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 140(2017):510-527.