文献类型：期刊文献

英文题名：Acenaphtho[1,2-b]pyrrole-Based Selective Fibroblast Growth Factor Receptors 1 (FGFR1) Inhibitors: Design, Synthesis, and Biological Activity

作者：Chen, Zhuo[1,2];Wang, Xin[2];Zhu, Weiping[2];Cao, Xianwen[2];Tong, Linjiang[1];Li, Honglin[2];Xie, Hua[1];Xu, Yufang[2];Tan, Shaoying[2];Kuang, Dong[2];Ding, Jian[1];Qian, Xuhong[2]

机构：[1]Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China;[2]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab Chem Biol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China

年份：2011

卷号：54

期号：11

起止页码：3732

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000291082500004)】；

基金：This work was financially supported by the Key New Drug Creation and Manufacturing Program (Grants 2009ZX09103-001 and 2009ZX09103-102), the National High Technology Research and Development Program of China (863 Program 2011AA10A207), the China 111 Project (Grant B07023), the Shanghai Leading Academic Discipline Project (Grant B507), and the Fundamental Research Funds for the Central Universities.

语种：英文

摘要：A novel series of acenaphtho[1,2-b]pyrrole derivatives as potent and selective inhibitors of fibroblast growth factor receptor 1 (FGFR1) were designed and synthesized. In silico target prediction revealed that tyrosine kinases might be the potential targets of the representative compound 2, which was subsequently validated by enzyme linked immunosorbent assay (ELISA) for its selective and active FGFR1 inhibition of various tyrosine kinases. The structure activity relationship (SAR) analysis aided by molecular docking simulation in the ATP binding site demonstrated that acenaphtho[1,2-b]pyrrole carboxylic acid esters (2-5) are potent inhibitors of FGFR1 with IC50 values ranging from 19 to 77 nM. Furthermore, these compounds exhibited favorable growth inhibition property against FGFR-expressing cancer cell lines with IC50 values ranging from micromolar to submicromolar. Western blotting analysis showed that compounds 2, 3, and 2b inhibited activation of FGFR1 and extracellular-signal regulated kinase 1/2 (Erk1/2).