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.

肝细胞癌（Hepatocellular carcinoma, HCC）是最为常见的肝癌类型，占所有肝癌病例的90%。约30%确诊为HCC的患者，其肿瘤存在成纤维细胞生长因子19（FGF19）-成纤维细胞生长因子受体4（FGFR4）通路的异常表达，该通路属于致癌驱动通路。因此，采用选择性FGFR4抑制剂调控FGF19-FGFR4信号通路，有望成为HCC的潜在治疗手段。本文报道了一类含有2,6-萘啶骨架的新型FGFR4抑制剂的设计与合成。化合物11对Huh7细胞系展现出纳摩尔级的抑制活性，且对FGFR1-3具有优异的选择性，其活性与参比标准药物菲索加替尼（8）相当。此外，化合物11在Huh7和Hep3B HCC异种移植小鼠模型中展现出显著的抗肿瘤疗效。进一步的原位小鼠模型生物发光成像实验证实，化合物11可作为治疗HCC的潜在候选药物。