Design, Synthesis, and Biological Evaluation of Aminoindazole Derivatives as Highly Selective Covalent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR4

Aberrant FGF19/FGFR4 signaling has been shown to bean oncogenic driver of growth and survival in human hepatocellularcarcinoma (HCC) with several pan-FGFR inhibitors and FGFR4-selective inhibitors currently being evaluated in the clinic. However,FGFR4 gatekeeper mutation induced acquired resistance remains anunmet clinical challenge for HCC treatment. Thus, a series ofaminoindazole derivatives were designed and synthesized as newirreversible inhibitors of wild-type and gatekeeper mutant FGFR4.One representative compound (7v) exhibited excellent potency againstFGFR4, FGFR4V550L, and FGFR4V550Mwith nanomolar activity in boththe biochemical and cellular assays while sparing FGFR1/2/3. Whilecompound7vdemonstrated modestin vivoantitumor efficacy in nudemice bearing the Huh-7 xenograft model consistent with its unfavorable pharmacokinetic properties, it provides a promising new starting point for future drug discovery combating FGFR4 gatekeeper mediated resistance in HCC patients

Automated summary

Aberrant FGF19/FGFR4 signaling is a carcinogenic driver of growth and survival in human hepatocellular carcinoma (HCC). FGFR4 gatekeeper mutation-induced acquired resistance is a clinical challenge for HCC treatment. A new series of irreversible inhibitors were designed and synthesized to target both wild-type and gatekeeper mutant FGFR4, providing a promising starting point for future drug discovery combating FGFR4 gatekeeper-mediated resistance in HCC patients.