Fibroblast Growth Factor Receptor 4 (FGFR4) Selective Inhibitors as Hepatocellular Carcinoma Therapy: Advances and Prospects
Fibroblast Growth Factor Receptor 4 (FGFR4) Selective Inhibitors as Hepatocellular Carcinoma Therapy: Advances and Prospects
复制标题
成纤维细胞生长因子受体 4 (FGFR4) 选择性抑制剂作为肝细胞癌治疗：进展与前景
DOI：
10.1021/acs.jmedchem.8b01531
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发表时间：
2019-03-28
影响因子：
7.3
通讯作者：
Ding, Ke
中科院分区：
文献类型：
--
作者：
Lu, Xiaoyun;Chen, Hao;Ding, Ke
肝细胞癌（HCC）是一种治疗选择有限且预后特别差的致死性疾病。通过成纤维细胞生长因子受体4（FGFR 4）的异常成纤维细胞生长因子19（FGF 19）信号转导已被鉴定为一部分HCC患者的致癌驱动因子。因此，FGFR 4是治疗具有异常FGF 19-FGFR 4信号传导的HCC的有希望的靶标，并且几种FGFR 4抑制剂已经进入临床试验。本文综述了FGFR 4抑制剂的最新研究进展，包括已知的药效团、结合模式、选择性和临床意义，以及在已知的泛FGFR抑制剂中引入丙烯酰胺靶向FGFR 4的Cys 552以提供选择性共价FGFR 4抑制剂的优化策略。
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.