Zhong Zhenpeng, Shi Liyang, Fu Tiancheng, Huang Jiajun, Pan Zhengying
State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen 518055, China.
J Med Chem. 2022 May 26;65(10):7278-7295. doi: 10.1021/acs.jmedchem.2c00255. Epub 2022 May 13.
Fibroblast growth factor receptor 4 (FGFR4) has been identified as a potential target for the treatment of hepatocellular carcinoma (HCC) with aberrant FGFR4 signaling because of its important role in HCC progression and development. Several FGFR4 inhibitors are under clinical development. Using a 7-azaindole scaffold, we discovered a series of novel selective and covalent FGFR4 inhibitors by performing a structure-based design approach. Representative compounds and exhibited potent FGFR4 inhibition and high selectivity among kinases. Western blot analysis showed that compounds and significantly inhibited the FGF19/FGFR4 signaling pathway in HuH-7 cells and effectively suppressed the proliferation of HuH-7 HCC cells and MDA-MB-453 breast cancer cells. Moreover, compound exhibited significant in vivo antitumor activity in a mouse HuH-7 xenograft model. Thus, compound and the 7-azaindole scaffold can be applied to develop anticancer agents for the treatment of cancers characterized by aberrant FGFR4 signaling.
成纤维细胞生长因子受体4（FGFR4）因其在肝细胞癌（HCC）进展和发展中的重要作用，已被确定为治疗具有异常FGFR4信号传导的肝细胞癌的潜在靶点。几种FGFR4抑制剂正在进行临床开发。通过基于结构的设计方法，我们使用7-氮杂吲哚支架发现了一系列新型的选择性和共价FGFR4抑制剂。代表性化合物 和 在激酶中表现出强大的FGFR4抑制作用和高选择性。蛋白质免疫印迹分析表明，化合物 和 显著抑制HuH-7细胞中的FGF19/FGFR4信号通路，并有效抑制HuH-7肝癌细胞和MDA-MB-453乳腺癌细胞的增殖。此外，化合物 在小鼠HuH-7异种移植模型中表现出显著的体内抗肿瘤活性。因此，化合物 和7-氮杂吲哚支架可用于开发抗癌药物，以治疗以异常FGFR4信号传导为特征的癌症。
