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

文献类型：期刊论文

作者Liu, Yang1; Peng, Xia2; Guan, Xiaocong1; Lu, Dong1; Xi, Yong2; Jin, Shiyu1; Chen, Hui2; Zeng, Limin1; Ai, Jing2; Geng, Meiyu2
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2017-01-27
卷号126页码:122-132
关键词FGFR KDR Inhibitor Anticancer Ponatinib
ISSN号0223-5234
DOI10.1016/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.
WOS关键词ADVANCED SOLID TUMORS ; BCR-ABL KINASE ; TYROSINE KINASE ; SELECTIVE INHIBITOR ; BREAST-CANCER ; RESISTANCE ; DESIGN ; MODELS ; MUTANT ; AMPLIFICATION
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研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000396804600012
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
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.

入库方式： OAI收割

来源：上海药物研究所

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