Design, synthesis and biological evaluation of novel FGFR inhibitors bearing an indazole scaffold
文献类型：期刊论文
| 作者 | Liu, Jian1; Peng, Xia2; Dai, Yang2; Zhang, Wei1; Ren, Sumei1; Ai, Jing2 ; Geng, Meiyu2; Li, Yingxia1
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| 刊名 | ORGANIC & BIOMOLECULAR CHEMISTRY
 |
| 出版日期 | 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). |
| WOS关键词 | GROWTH-FACTOR RECEPTOR ; TYROSINE KINASE DOMAIN ; SELECTIVE INHIBITOR ; POTENT ; CANCER ; FUSIONS ; FAMILY |
| 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研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000358243200008 |
| 出版者 | ROYAL SOC CHEMISTRY |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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