posted on 2024-02-13, 12:35authored byFang Yang, Qianmeng Lin, Xiaojuan Song, Huisi Huang, Xiaojuan Chen, Jianwen Tan, Yun Li, Yang Zhou, Zhengchao Tu, Hongli Du, Zhi-min Zhang, Raquel Ortega, Xiaojing Lin, Adam V. Patterson, Jeff B. Smaill, Yongheng Chen, Xiaoyun Lu
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.