Discovery of Novel 7‑Azaindole Derivatives as Selective Covalent Fibroblast Growth Factor Receptor 4 Inhibitors for the Treatment of Hepatocellular Carcinoma

Fibroblast growth factor receptor
4 (FGFR4) has been identified
as a potential target for the treatment of hepatocellular carcinoma
(HCC) with aberrant FGFR4 signaling because of its important role
in HCC progression and development. Several FGFR4 inhibitors are under
clinical development. Using a 7-azaindole scaffold, we discovered
a series of novel selective and covalent FGFR4 inhibitors by performing
a structure-based design approach. Representative compounds 24 and 30 exhibited potent FGFR4 inhibition and
high selectivity among kinases. Western blot analysis showed that
compounds 24 and 30 significantly inhibited
the FGF19/FGFR4 signaling pathway in HuH-7 cells and effectively suppressed
the proliferation of HuH-7 HCC cells and MDA-MB-453 breast cancer
cells. Moreover, compound 30 exhibited significant in
vivo antitumor activity in a mouse HuH-7 xenograft model. Thus, compound 30 and the 7-azaindole scaffold can be applied to develop
anticancer agents for the treatment of cancers characterized by aberrant
FGFR4 signaling.