成纤维细胞生长因子受体4
肝细胞癌
FGF19型
化学
癌症研究
细胞培养
成纤维细胞生长因子
成纤维细胞
药理学
成纤维细胞生长因子受体
受体
生物化学
体外
生物
遗传学
作者
Renata Rezende Miranda,Ying Fu,Xiaojuan Chen,John Perino,Ping Cao,John D. Carpten,Yongheng Chen,Chao Zhang
标识
DOI:10.1021/acs.jmedchem.0c00044
摘要
Abnormal activation of the fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) signaling pathway has been shown to drive the proliferation of a significant portion of hepatocellular carcinoma (HCC). Resistance and toxicity are serious drawbacks that have been observed upon use of the current first- and second-line treatment options for HCC, therefore warranting the investigation of alternative therapeutic approaches. We report the development and biological characterization of a covalent inhibitor that is highly potent and exquisitely specific to FGFR4. The crystal structure of this inhibitor in complex with FGFR4 was solved, confirming its covalent binding and revealing its binding mode. We also describe the first clickable probe for FGFR4 that can be used to directly measure target engagement in cells. Our compound exhibited great antitumor activity in HCC cell lines and tumor xenograft models. These results provide evidence of a promising therapeutic lead for the treatment of a subset of HCC patients.
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