School of Pharmacy , Jinan University , No. 601 Huangpu Avenue West , Guangzhou 510632 , China.
Maurice Wilkins Centre for Molecular Biodiscovery , University of Auckland , Private Bag 92019 , Auckland 1142 , New Zealand.
J Med Chem. 2019 Mar 28;62(6):2905-2915. doi: 10.1021/acs.jmedchem.8b01531. Epub 2018 Nov 16.
Hepatocellular carcinoma (HCC) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Aberrant fibroblast growth factor 19 (FGF19) signaling through fibroblast growth factor receptor 4 (FGFR4) has been identified as an oncogenic driver for a subset of patients with HCC. FGFR4 is therefore a promising target for the treatment of HCC harboring aberrant FGF19-FGFR4 signaling, and several FGFR4 inhibitors have advanced to clinical trial. In this review, we summarize the latest developments in FGFR4 inhibitors, including the known pharmacophores, their binding mode, selectivity, and clinical implications, as well as the optimization strategy of introducing an acrylamide into a known pan-FGFR inhibitor targeting Cys552 of FGFR4 to provide selective covalent FGFR4 inhibitors.
肝细胞癌（HCC）是一种致命疾病，治疗选择有限，预后特别差。异常的成纤维细胞生长因子 19（FGF19）通过成纤维细胞生长因子受体 4（FGFR4）信号已被确定为 HCC 患者亚群的致癌驱动因素。因此，FGFR4 是治疗携带异常 FGF19-FGFR4 信号的 HCC 的有前途的靶点，几种 FGFR4 抑制剂已进入临床试验。在这篇综述中，我们总结了 FGFR4 抑制剂的最新进展，包括已知的药效团、它们的结合模式、选择性和临床意义，以及将丙烯酰胺引入针对 FGFR4 的 Cys552 的已知泛 FGFR 抑制剂以提供选择性共价 FGFR4 抑制剂的优化策略。
