VHL-based PROTACs turn a pan-FGFR inhibitor into FGFR2/4-selective degraders
- The team linked an in-house pan-FGFR inhibitor to a VHL ligand, building a PROTAC series.
- Two lead compounds degraded FGFR2 and FGFR4 selectively through the ubiquitin-proteasome system and showed potent antiproliferative effects in cells.
- In a gastric cancer xenograft model they shrank tumors with target degradation, and ternary complex modeling rationalized the isoform selectivity. The authors describe these as the first FGFR4-directed PROTACs.
💡 Points Based on the abstract
A pan-FGFR warhead yielding FGFR2/4-selective degraders is the real story: degradation selectivity comes from ternary-complex geometry, not binding affinity, so the SAR lives in the linker and VHL exit vector. FGFR4 has been mostly covalent-inhibitor territory, so this is a genuinely different handle. I'd check FGFR1/3 sparing and hook effect.
Identification of selective FGFR2/4 degraders with potent antiproliferative activity ↗