Covalent indolinone pan-FGFR inhibitor stays potent against gatekeeper and brake resistance mutants
- Structure-guided design produced a 3-(aminobenzylidene)indolin-2-one series that binds FGFR1-4 irreversibly, aimed at resistance to approved FGFR drugs.
- The lead compound 9v inhibits all four isoforms at single-digit nanomolar levels and suppresses FGFR-dependent cancer cell growth even more strongly.
- It keeps sub-nanomolar activity on gatekeeper and molecular-brake mutants; mass spectrometry confirmed covalent labeling of FGFR3.
- Tumor growth was clearly reduced in a bladder cancer xenograft.
💡 Points Based on the abstract
Which cysteine is 9v actually labeling, and what else does it label? Retained potency on gatekeeper and brake mutants is encouraging, but a covalent warhead invites off-target cysteine reactivity. I'd want a cysteine-to-serine mutant control, kinome-wide profiling and glutathione reactivity data, plus a head-to-head against futibatinib, before trusting the selectivity story.