Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang, 325035, China.
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang, 325035, China.
Eur J Med Chem. 2023 Nov 5;259:115703. doi: 10.1016/j.ejmech.2023.115703. Epub 2023 Aug 4.
Aberrant FGFR4 signaling has been implicated in the development of several cancers, making FGFR4 a promising target for cancer therapy. Several FGFR4-selective inhibitors have been developed, yet none of them have been approved. Herein, we report a novel series of 1,6-naphthyridine-2-one derivatives as potent and selective inhibitors targeting FGFR4 kinase. Preliminary structure-activity relationship analysis was conducted. The screening cascades revealed that 19g was the preferred compound among the prepared series. 19g demonstrated excellent kinase selectivity and substantial cytotoxic effect against all tested colorectal cancer cell lines. 19g induced significant tumor inhibition in a HCT116 xenograft mouse model without any apparent toxicity. Notably, 19g exhibited excellent potency in disrupting the phosphorylation of FGFR4 and downstream signaling proteins mediated by FGF18 and FGF19. Compound 19g might be a potential antitumor drug candidate for the treatment of colorectal cancer.
异常的 FGFR4 信号已被牵涉到多种癌症的发展中，这使得 FGFR4 成为癌症治疗的一个有前途的靶点。已经开发了几种 FGFR4 选择性抑制剂，但没有一种得到批准。在此，我们报告了一系列新型的 1,6-萘啶-2-酮衍生物，它们是针对 FGFR4 激酶的有效且选择性的抑制剂。进行了初步的构效关系分析。筛选级联反应表明，19g 是所制备系列中首选的化合物。19g 对所有测试的结直肠癌细胞系均表现出优异的激酶选择性和显著的细胞毒性作用。19g 在 HCT116 异种移植小鼠模型中诱导了显著的肿瘤抑制作用，没有明显的毒性。值得注意的是，19g 表现出了极好的效力，可破坏 FGF18 和 FGF19 介导的 FGFR4 磷酸化及其下游信号蛋白。化合物 19g 可能是一种用于治疗结直肠癌的潜在抗肿瘤药物候选物。
