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.

中文翻译：

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发现 2,6-萘啶类似物作为肝细胞癌选择性 FGFR4 抑制剂


肝细胞癌 (HCC) 是最常见的肝癌类型，占 90% 的肝癌病例。大约 30% 诊断为 HCC 的患者被确定为成纤维细胞生长因子 19 (FGF19) - 成纤维细胞生长因子受体 4 (FGFR4) 的异常表达，作为致癌驱动途径。因此，用选择性 FGFR4 抑制剂控制 FGF19-FGFR4 信号通路可能是治疗 HCC 的一种有前景的疗法。我们在此公开了包含2,6-萘啶支架的新型FGFR4抑制剂的设计和合成。化合物 11 对 Huh7 细胞系表现出纳摩尔级效力，并且对 FGFR1-3 具有高选择性，与作为参考标准的 fisogatinib (8) 相当。此外，化合物 11 在 Huh7 和 Hep3B HCC 异种移植小鼠模型中表现出显着的抗肿瘤功效。此外，原位小鼠模型的生物发光成像实验支持化合物 11 可以被认为是治疗 HCC 的有希望的候选者。