Design, synthesis, and biological evaluation of the first fibroblast growth factor receptor 4 PROTAC degrader

Aberrant activation of the FGFR4 signaling pathway, often driven by FGFR4 genetic alterations, has been implicated in the progression of hepatocellular carcinoma (HCC), highlighting FGFR4 as a promising therapeutic target for FGFR4-driven HCC. Although numerous selective covalent FGFR4 inhibitors have been discovered, developing FGFR4 PROTACs could offer great advantages as an alternative and complementary strategy for HCC therapy. In this study, we have designed a series of covalent degraders by conjugating the FGFR4-selective inhibitor H3B-6527 to E3 ubiquitin ligase-recruiting ligands via diverse linkers. Among them, we identified compound V1 as the first PROTAC capable of degrading FGFR4, with a DC₅₀ value of 0.84 μM and Dmax rate of 80%. Further evaluation demonstrated that V1 promotes efficient and sustained FGFR4 degradation through a ubiquitin-proteasome system (UPS)-dependent pathway and exhibited moderate inhibitory effects on cell proliferation in JHH-7 cells. Moreover, the covalent binding model of compound V1 with FGFR4 was also characterized by LC-MS/MS. These findings suggest that V1 is a promising lead compound for the development of FGFR4-targeted PROTACs.