西亚试剂：Acenaphtho[1,2-b]pyrrole-Based Selective Fibroblast Growth

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

Zhuo Chen, Xin Wang, Weiping Zhu, Xianwen Cao, Linjiang Tong, Honglin Li, Hua Xie, Yufang Xu, Shaoying Tan, Dong Kuang, Jian Ding, and Xuhong Qian

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 (E...