Development of a Potent and Specific FGFR4 Inhibitor for the Treatment of Hepatocellular Carcinoma

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.