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 be an oncogenic
driver of growth and survival in human hepatocellular carcinoma (HCC)
with several pan-FGFR inhibitors and FGFR4-selective inhibitors currently
being evaluated in the clinic. However, FGFR4 gatekeeper mutation
induced acquired resistance remains an unmet clinical challenge for
HCC treatment. Thus, a series of aminoindazole derivatives were designed
and synthesized as new irreversible inhibitors of wild-type and gatekeeper
mutant FGFR4. One representative compound (7v) exhibited
excellent potency against FGFR4, FGFR4V550L, and FGFR4V550M with nanomolar activity in both the biochemical and cellular
assays while sparing FGFR1/2/3. While compound 7v demonstrated
modest in vivo antitumor efficacy in nude mice 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.