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.
Bioorg Chem. 2022 Apr;121:105673. doi: 10.1016/j.bioorg.2022.105673. Epub 2022 Feb 12.
Fibroblast growth factor receptor 4 (FGFR4) together with co-receptors modulate the activation of downstream proteins that regulate fundamental processes, and elevated FGFR4 activity is associated with Hepatocellular Carcinoma (HCC). Hence, FGFR4 is a promising therapeutic target for HCC. Based on BLU9931, we designed and synthesized a series of phenylquinazoline derivatives as novel inhibitors of FGFR4 through the covalent reversible strategy. Among them, a novel compound (C3) showed FGFR4 and cell proliferation inhibitory activity. Cellular mechanism studies demonstrated that compound C3 induced apoptosis via the FGFR4 signaling pathway blockage. Further mechanism study showed that C3 has the reversible covalent binding capacity, could be used as a reference for the development of novel FGFR4 covalent reversible inhibitors.
成纤维细胞生长因子受体 4（FGFR4）与共受体一起调节下游蛋白的激活，这些蛋白调节基本过程，而升高的 FGFR4 活性与肝细胞癌（HCC）有关。因此，FGFR4 是 HCC 的一个有前途的治疗靶点。基于 BLU9931，我们通过共价可逆策略设计并合成了一系列苯并喹唑啉衍生物作为新型 FGFR4 抑制剂。其中，一种新型化合物（C3）显示出 FGFR4 和细胞增殖抑制活性。细胞机制研究表明，化合物 C3 通过 FGFR4 信号通路阻断诱导细胞凋亡。进一步的机制研究表明，C3 具有可逆的共价结合能力，可作为开发新型 FGFR4 共价可逆抑制剂的参考。
