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

Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, accounting for 90% of cases. About 30% of HCC patients exhibit aberrant expression of the fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4) signaling pathway, which acts as an oncogenic driver. Targeting the FGF19-FGFR4 pathway with selective FGFR4 inhibitors could offer a promising treatment approach for HCC. In this study, we present the development of novel FGFR4 inhibitors featuring a 2,6-naphthyridine scaffold. Compound 11 demonstrated nanomolar potency against Huh7 cell lines and high selectivity for FGFR4 over FGFR1-3, comparable to the reference standard fisogatinib (8). Additionally, compound 11 exhibited significant antitumor efficacy in Huh7 and Hep3B HCC xenograft mouse models. Bioluminescence imaging in an orthotopic mouse model further supports the potential of compound 11 as a promising candidate BLU-554 for HCC treatment.