Identification of selective FGFR2/4 degraders with potent antiproliferative activity.

The FGF/FGFR pathway plays critical roles in tumorigenesis, making FGFRs attractive therapeutic targets. Based on a novel pan-FGFR inhibitor previously developed by our group, we designed and synthesized a series of PROTACs by conjugating this inhibitor with a VHL E3 ligase ligand. Among them, compounds 20i and 24g were identified as potent and selective degraders of FGFR2 and FGFR4, exhibiting nanomolar antiproliferative activity and modest microsomal stability. Mechanistic studies confirmed that degradation occurs via the ubiquitin-proteasome system. In SNU-16 xenograft models, both 20i and 24g demonstrated potent antitumor activity accompanied by FGFR2/4 degradation and suppression of downstream signaling. Ternary complex modeling elucidated the structural basis for isoform selectivity. This work represents the first report of FGFR4-targeted PROTACs and demonstrates that rational design can convert non-selective inhibitors into highly specific degraders, offering a novel therapeutic strategy for cancer treatment.