A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFR(L858R/T790M) mutant with improved pharmacokinetic properties

doi:10.1016/j.ejmech.2016.12.006

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	A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFR(L858R/T790M) mutant with improved pharmacokinetic properties
	Yu, Lei 1,2; Huang, Minhao 1,2; Xu, Tianfeng 1,2; Tong, Linjiang 4; Yan, Xiao-e 5,6; Zhang, Zhang 1; Xu, Yong 1; Yun, Caihong ; Xie, Hua4 ; Ding, Ke 1,3
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2017-01-27
卷号	126 页码:1107-1117
关键词	EGFR(T790M) mutant Pyrido[2,3-d]pyrimidin-7-ones Pharmacokinetic property NSCLC Irreversible inhibitor
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2016.12.006
文献子类	Article
英文摘要	Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFR(T790M) inhibitors with improved pharmacokinetic properties. One of the most promising compound 9s potently suppressed EGFR(L858R/T790M) kinase and inhibited the proliferation of H1975 cells with IC50 values of 2.0 nM and 40 nM, respectively. The compound dose-dependently induced reduction of the phosphorylation of EGFR and downstream activation of ERIC in NCI-H1975 cells. It also exhibited moderate plasma exposure after oral administration and an oral bioavailability value of 16%. Compound 9s may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients. (C) 2016 Published by Elsevier Masson SAS.
资助项目	National High Technology Research and Development (863) for Young Scientists program[2015AA020906] ; Guangdong Province[2015A030306042] ; Guangdong Province[2014TQ01R341] ; Guangdong Province[2015A030312014] ; Guangzhou City[201508030036] ; Guangzhou City[201506010086]
WOS关键词	GROWTH-FACTOR RECEPTOR ; CELL LUNG-CANCER ; 1ST GLOBAL APPROVAL ; EGFR INHIBITORS ; TYROSINE KINASE ; T790M-MEDIATED RESISTANCE ; BIOLOGICAL EVALUATION ; DISCOVERY ; POTENT ; PERSPECTIVES
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:000396804600085
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275667]
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	Xie, Hua; Ding, Ke; Lu, Xiaoyun
作者单位	1.Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, 190 Kaiyuan Ave, Guangzhou 510530, Peoples R China; 2.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China; 3.Jinan Univ, Sch Pharm, 601 Huangpu Ave West, Guangzhou 510632, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd,Zhangjiang Hi Tech Pk, Shanghai 201203, Peoples R China; 5.Peking Univ, Hlth Sci Ctr, Inst Syst Biomed, Beijing 100191, Peoples R China; 6.Peking Univ, Hlth Sci Ctr, Dept Biophys, Beijing 100191, Peoples R China
推荐引用方式 GB/T 7714	Yu, Lei,Huang, Minhao,Xu, Tianfeng,et al. A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFR(L858R/T790M) mutant with improved pharmacokinetic properties[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2017,126:1107-1117.
APA	Yu, Lei.,Huang, Minhao.,Xu, Tianfeng.,Tong, Linjiang.,Yan, Xiao-e.,...&Lu, Xiaoyun.(2017).A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFR(L858R/T790M) mutant with improved pharmacokinetic properties.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,126,1107-1117.
MLA	Yu, Lei,et al."A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFR(L858R/T790M) mutant with improved pharmacokinetic properties".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 126(2017):1107-1117.