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

详细信息    查看全文

• 作者：Zhuo Chen ; Xin Wang ; Weiping Zhu ; Xianwen Cao ; Linjiang Tong ; Honglin Li ; Hua Xie ; Yufang Xu ; Shaoying Tan ; Dong Kuang ; Jian Ding ; Xuhong Qian
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 9, 2011
• 年：2011
• 卷：54
• 期：11
• 页码：3732-3745
• 全文大小：1209K
• 年卷期：v.54,no.11(June 9, 2011)
• ISSN：1520-4804

文摘

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鈥揳ctivity relationship (SAR) analysis aided by molecular docking simulation in the ATP-binding site demonstrated that acenaphtho[1,2-b]pyrrole carboxylic acid esters (2鈥?b>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).