Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
Eur J Med Chem. 2021 Dec 5;225:113794. doi: 10.1016/j.ejmech.2021.113794. Epub 2021 Aug 19.
Aberrant activation of the fibroblast growth factor 19-fibroblast growth factor receptor 4 (FGF19-FGFR4) signaling pathway has been proved to promote hepatocellular carcinoma (HCC) proliferation. It is assumed that the first FGFR4 inhibitor BLU9931 did not enter clinical studies, presumably due to its rapid metabolism in liver microsomes. Here, we report the development of series of quinazoline derivatives based on FGFR4 inhibitor BLU9931 through structural modification of its solvent region pocket to minimize its potential metabolic liability. Among them, compound 35a exhibited comparable or superior kinase inhibitory activity (IC50 = 8.5 nM) and selectivity in cells. More importantly, compound 35a improved liver microsomes stability compared to BLU9931. Cellular mechanistic studies demonstrated that 35a induced apoptosis via the FGFR4 signaling pathway blockage. In addition, the computational simulation revealed the possible binding mode to FGFR4 protein, which provides a plausible explanation of high potent and metabolic stability.
异常激活成纤维细胞生长因子 19-成纤维细胞生长因子受体 4（FGF19-FGFR4）信号通路已被证明可促进肝细胞癌（HCC）增殖。据推测，第一个 FGFR4 抑制剂 BLU9931 并未进入临床研究，可能是由于其在肝微粒体中快速代谢。在这里，我们通过对 FGFR4 抑制剂 BLU9931 的溶剂区域口袋进行结构修饰，开发了一系列基于喹唑啉衍生物的化合物，以尽量降低其潜在的代谢风险。其中，化合物 35a 在细胞中表现出相当或更高的激酶抑制活性（IC50=8.5 nM）和选择性。更重要的是，与 BLU9931 相比，化合物 35a 提高了肝微粒体的稳定性。细胞机制研究表明，35a 通过阻断 FGFR4 信号通路诱导细胞凋亡。此外，计算模拟揭示了与 FGFR4 蛋白的可能结合模式，这为高活性和代谢稳定性提供了合理的解释。
