Discovery of novel Ponatinib analogues for reducing KDR activity as potent FGFRs inhibitors

doi:10.1016/j.ejmech.2016.10.003

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	Discovery of novel Ponatinib analogues for reducing KDR activity as potent FGFRs inhibitors
	Liu, Yang 1; Peng, Xia 2; Guan, Xiaocong 1; Lu, Dong 1; Xi, Yong 2; Jin, Shiyu 1; Chen, Hui 2; Zeng, Limin 1; Ai, Jing2 ; Geng, Meiyu2
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2017-01-27
卷号	126 页码:122-132
关键词	FGFR KDR Inhibitor Anticancer Ponatinib
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2016.10.003
文献子类	Article
英文摘要	FGF receptors (FGFRs) are tyrosine kinases that are overexpressed in diverse tumors by genetic alterations such as gene amplifications, somatic mutations and translocations. Owing to this characteristic, FGFRs are attractive targets for cancer treatment. It has been demonstrated that most multi-targeted, ATP competitive tyrosine kinase inhibitors are active against FGFRs as well as other kinases. The design of new and more selective inhibitors of FGFRs, which might be reduced off-target and side effects, is a difficult yet significant challenge. The results of the current investigation, show that novel Ponatinib analogues are highly active as FGFR inhibitors and that they possess reduced kinase insert domain receptor (KDR) activities. Observations made in a structure and activity relationship (SAR) investigation led to the development of a promising, orally available lead compound 4, which displays a 50-100 fold in vitro selectivity for inhibition of FGFR1-3 over KDR. In addition, biological evaluation of compound 4 showed that it displays significant antitumor activities in FGFR1-amplificated H1581 and FGFR2amplificated SNU-16 xenograft models. (C) 2016 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[81225022] ; National Natural Science Foundation of China[81473243] ; National Natural Science Foundation of China[8132109] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" of China[2012ZX09301001-007] ; SA-SIBS Scholarship Program[00000000]
WOS关键词	ADVANCED SOLID TUMORS ; BCR-ABL KINASE ; TYROSINE KINASE ; SELECTIVE INHIBITOR ; BREAST-CANCER ; RESISTANCE ; DESIGN ; MODELS ; MUTANT ; AMPLIFICATION
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:000396804600012
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275665]
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药物化学研究室
通讯作者	Ai, Jing; Geng, Meiyu; Hu, Youhong
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 ZuChongZhi Rd, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, 555 ZuChongZhi Rd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Liu, Yang,Peng, Xia,Guan, Xiaocong,et al. Discovery of novel Ponatinib analogues for reducing KDR activity as potent FGFRs inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2017,126:122-132.
APA	Liu, Yang.,Peng, Xia.,Guan, Xiaocong.,Lu, Dong.,Xi, Yong.,...&Hu, Youhong.(2017).Discovery of novel Ponatinib analogues for reducing KDR activity as potent FGFRs inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,126,122-132.
MLA	Liu, Yang,et al."Discovery of novel Ponatinib analogues for reducing KDR activity as potent FGFRs inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 126(2017):122-132.