Department of Chemistry and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, California 90089, United States.
Department of Oncology, NHC Key Laboratory of Cancer Proteomics and Laboratory of Structural Biology, Central South University, Changsha, Hunan 410008, China.
J Med Chem. 2020 Oct 22;63(20):11484-11497. doi: 10.1021/acs.jmedchem.0c00044. Epub 2020 Oct 8.
Abnormal activation of the fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) signaling pathway has been shown to drive the proliferation of a significant portion of hepatocellular carcinoma (HCC). Resistance and toxicity are serious drawbacks that have been observed upon use of the current first- and second-line treatment options for HCC, therefore warranting the investigation of alternative therapeutic approaches. We report the development and biological characterization of a covalent inhibitor that is highly potent and exquisitely specific to FGFR4. The crystal structure of this inhibitor in complex with FGFR4 was solved, confirming its covalent binding and revealing its binding mode. We also describe the first clickable probe for FGFR4 that can be used to directly measure target engagement in cells. Our compound exhibited great antitumor activity in HCC cell lines and tumor xenograft models. These results provide evidence of a promising therapeutic lead for the treatment of a subset of HCC patients.
成纤维细胞生长因子 19（FGF19）/成纤维细胞生长因子受体 4（FGFR4）信号通路的异常激活已被证明可驱动肝癌（HCC）的显著增殖。在使用当前 HCC 的一线和二线治疗方案时，已经观察到耐药性和毒性是严重的缺陷，因此需要研究替代的治疗方法。我们报告了一种共价抑制剂的开发和生物学特性，该抑制剂对 FGFR4 具有高度的效力和特异性。该抑制剂与 FGFR4 复合物的晶体结构已被解决，证实了其共价结合并揭示了其结合模式。我们还描述了第一个可点击的 FGFR4 探针，可用于直接测量细胞中的靶标结合。我们的化合物在 HCC 细胞系和肿瘤异种移植模型中表现出很强的抗肿瘤活性。这些结果为治疗一部分 HCC 患者提供了有前途的治疗先导物的证据。
