Discovery of 2,6-Naphthyridine Analogues as Selective FGFR4 Inhibitors for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is
the most common type of liver
cancer and is responsible for 90% of cases. Approximately 30% of patients
diagnosed with HCC are identified as displaying an aberrant expression
of fibroblast growth factor 19 (FGF19)–fibroblast growth factor
receptor 4 (FGFR4) as an oncogenic-driver pathway. Therefore, the
control of the FGF19-FGFR4 signaling pathway with selective FGFR4
inhibitors can be a promising therapy for the treatment of HCC. We
herein disclose the design and synthesis of novel FGFR4 inhibitors
containing a 2,6-naphthyridine scaffold. Compound 11 displayed
a nanomolar potency against Huh7 cell lines and high selectivity over
FGFR1–3 that were comparable to that of fisogatinib (8) as a reference standard. Additionally, compound 11 demonstrated remarkable antitumor efficacy in the Huh7 and Hep3B
HCC xenograft mouse model. Moreover, bioluminescence imaging experiments
with the orthotopic mouse model support that compound 11 can be considered a promising candidate for treating HCC.