Design, synthesis and biological evaluation of quinazoline derivatives as potent and selective FGFR4 inhibitors

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. [Display omitted] •A series of quinazoline derivatives designed to minimize potential metabolism.•35a displayed good FGFR4 inhibitory activity (IC50 = 8.5 nM) and selectivity.•35a improved liver microsomes stability compared to BLU9931.•35a performed strong binding to FGFR4 by docking and dynamic simulation.