Development of a series of novel potent and selective irreversible covalent FGFR4 inhibitors with a mix-and-match strategy

Dysregulation of the FGF19/FGFR4 signaling pathway has been implicated in the development of hepatocellular carcinoma (HCC), making FGFR4 a promising therapeutic target. Several FGFR4 covalent inhibitors have been developed and tested in clinical trials but with limited success; therefore, new types of inhibitors are needed. Herein, we report a novel series of 7-azaindole-based compounds as potential type-II covalent inhibitors against FGFR4 kinase. Representative compound 10v exhibited potent FGFR4 inhibition (IC₅₀ = 1.2 nM) and a high selectivity among the tested kinases. In cells, compound 10v considerably inhibited the FGF19/FGFR4 signaling pathway, effectively suppressing the proliferation of the HuH-7 HCC cell line (GI₅₀ = 17 nM). Moreover, compound 10v exhibited significant in vivo antitumor activity in a HuH-7 mouse xenograft model. Thus, compound 10v is a promising lead compound for further drug development targeting FGFR4.

Fibroblast growth factor receptor 4; Hepatocellular carcinoma; Irreversible covalent inhibitor.