C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFR(T790M) mutant

doi:10.1039/c5md00208g

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	C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFR(T790M) mutant
	Xu, Tianfeng 1; Peng, Ting 2; Ren, Xiaomei 1; Zhang, Lianwen 1; Yu, Lei 1; Luo, Jinfeng 1; Zhang, Zhang 1; Tu, Zhengchao 1; Tong, Linjiang 2; Huang, Zhaoru 2
刊名	MEDCHEMCOMM
	2015
卷号	6 期号:9 页码:1693-1697
ISSN号	2040-2503
DOI	10.1039/c5md00208g
文献子类	Article
英文摘要	The development of specific kinase inhibitors has been a long-standing challenge in chemical biology and drug discovery. We have successfully discovered a series of C5-substituted pyrido[2,3-d] pyrimidin-7-ones as highly specific inhibitors against the clinical resistance-related EGFR(T790M) mutant. One of the most promising compounds, 9f, tightly binds to the EGFR(T790M) mutant and strongly inhibits its enzymatic function with an IC50 value of 0.80 nM, and displays an extraordinary target specificity with S(35) and S(10) selectivity scores of 0.005 and 0.000, respectively, in a kinase selectivity profiling study against 456 different kinases at 100 nM. The compound also selectively suppresses the proliferation of EGFR(T790M) mutated H1975 NSCLC cells with an IC50 value of 2.80 nM, but is significantly less toxic to cells with wild-type EGFR. Compound 9f may serve as a promising lead compound for drug discovery overcoming the acquired resistance of NSCLC patients without adverse toxicities.
资助项目	National Natural Science Foundation of China[81425021] ; National Natural Science Foundation of China[8173080] ; National Natural Science Foundation of China[81321092] ; 100 Distinguished Scientist Award of Guangdong Province (Nanyue-Baijie Award)[00000000] ; Key Project on Innovative Drug of Guangdong Province[00000000]
WOS关键词	CELL LUNG-CANCER ; FACTOR RECEPTOR THREONINE(790) ; BIOLOGICAL EVALUATION ; ACQUIRED-RESISTANCE ; PHARMACOKINETIC PROPERTIES ; METHIONINE(790) MUTANT ; EGFR MUTATION ; PHASE-II ; T790M ; TRIAL
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
语种	英语
出版者	ROYAL SOC CHEMISTRY
WOS记录号	WOS:000360639300015
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276707]
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
作者单位	1.Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, State Key Lab Resp Dis, Guangzhou 510530, Guangdong, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Xu, Tianfeng,Peng, Ting,Ren, Xiaomei,et al. C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFR(T790M) mutant[J]. MEDCHEMCOMM,2015,6(9):1693-1697.
APA	Xu, Tianfeng.,Peng, Ting.,Ren, Xiaomei.,Zhang, Lianwen.,Yu, Lei.,...&Ding, Ke.(2015).C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFR(T790M) mutant.MEDCHEMCOMM,6(9),1693-1697.
MLA	Xu, Tianfeng,et al."C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFR(T790M) mutant".MEDCHEMCOMM 6.9(2015):1693-1697.