Design, synthesis and biological evaluation of novel FGFR inhibitors bearing an indazole scaffold

doi:10.1039/c5ob00778j

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Design, synthesis and biological evaluation of novel FGFR inhibitors bearing an indazole scaffold
	Liu, Jian 1; Peng, Xia 2; Dai, Yang 2; Zhang, Wei 1; Ren, Sumei 1; Ai, Jing2 ; Geng, Meiyu2 ; Li, Yingxia 1
刊名	ORGANIC & BIOMOLECULAR CHEMISTRY
	2015
卷号	13 期号:28 页码:7643-7654
ISSN号	1477-0520
DOI	10.1039/c5ob00778j
文献子类	Article
英文摘要	Fibroblast growth factor receptor (FGFR) is a potential target for cancer therapy. Based on the structure of AZD4547 and NVPBGJ-398, we designed novel 1H-indazol-3-amine scaffold derivatives by utilizing scaffold hopping and molecular hybridization strategies. Consequently, twenty-eight new compounds were synthesized and evaluated for their inhibitory activity against FGFR1. Compound 7n bearing a 6-(3-methoxyphenyl)-1H-indazol-3-amine scaffold was first identified as a potent FGFR1 inhibitor, with good enzymatic inhibition (IC50 = 15.0 nM) and modest cellular inhibition (IC50 = 642.1 nM). The crystal structure of 7n bound to FGFR1 was obtained, which might provide a new basis for potent inhibitor design. Further structural optimization revealed that compound 7r stood out as the most potent FGFR1 inhibitor with the best enzyme inhibitory (IC50 = 2.9 nM) and cellular activity (IC50 = 40.5 nM).
资助项目	National Natural Science Foundation of China[81473243] ; National Natural Science Foundation of China[81321092] ; National Natural Science Foundation of China[91229205] ; National Science & Technology Major Project on 'Key New Drug Creation and Manufacturing Program'[2012ZX09301001-007]
WOS关键词	GROWTH-FACTOR RECEPTOR ; TYROSINE KINASE DOMAIN ; SELECTIVE INHIBITOR ; POTENT ; CANCER ; FUSIONS ; FAMILY
WOS研究方向	Chemistry
语种	英语
出版者	ROYAL SOC CHEMISTRY
WOS记录号	WOS:000358243200008
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276719]
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	Ai, Jing
作者单位	1.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Liu, Jian,Peng, Xia,Dai, Yang,et al. Design, synthesis and biological evaluation of novel FGFR inhibitors bearing an indazole scaffold[J]. ORGANIC & BIOMOLECULAR CHEMISTRY,2015,13(28):7643-7654.
APA	Liu, Jian.,Peng, Xia.,Dai, Yang.,Zhang, Wei.,Ren, Sumei.,...&Li, Yingxia.(2015).Design, synthesis and biological evaluation of novel FGFR inhibitors bearing an indazole scaffold.ORGANIC & BIOMOLECULAR CHEMISTRY,13(28),7643-7654.
MLA	Liu, Jian,et al."Design, synthesis and biological evaluation of novel FGFR inhibitors bearing an indazole scaffold".ORGANIC & BIOMOLECULAR CHEMISTRY 13.28(2015):7643-7654.