化学
体内
成纤维细胞生长因子受体4
肝细胞癌
FGF19型
药理学
生物化学
癌症研究
受体
成纤维细胞生长因子
成纤维细胞生长因子受体
医学
生物
生物技术
作者
Fang Yang,Qianmeng Lin,Xiaojuan Song,Huisi Huang,Xiaojuan Chen,Jianjun Tan,Yi Li,Yang Zhou,Zhengchao Tu,Hong Du,Zhimin Zhang,Raquel Ortega,Xiaojing Lin,Adam V. Patterson,Jeff B. Smaill,Yongheng Chen,Xiaoyun Lu
标识
DOI:10.1021/acs.jmedchem.3c01810
摘要
Fibroblast growth factor receptor 4 (FGFR4) has been considered as a potential anticancer target due to FGF19/FGFR4 mediated aberrant signaling in hepatocellular carcinoma (HCC). Several FGFR4 inhibitors have been reported, but none have gained approval. Herein, a series of 5-formyl-pyrrolo[3,2-b]pyridine-3-carboxamides and a series of 6-formylpyridyl ureas were characterized as selective reversible-covalent FGFR4 inhibitors. The representative 6-formylpyridyl urea 8z exhibited excellent potency against FGFR4WT, FGFR4V550L, and FGFR4V550M with IC50 values of 16.3, 12.6, and 57.3 nM, respectively. It also potently suppressed proliferation of Ba/F3 cells driven by FGFR4WT, FGFR4V550L, and FGFR4V550M, and FGFR4-dependent Hep3B and Huh7 HCC cells, with IC50 values of 1.2, 13.5, 64.5, 15.0, and 20.4 nM, respectively. Furthermore, 8z displayed desirable microsomal stability and significant in vivo efficacy in the Huh7 HCC cancer xenograft model in nude mice. The study provides a promising new lead for anticancer drug discovery directed toward overcoming FGFR4 gatekeeper mutation mediated resistance in HCC patients.
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