F-30 covalent inhibitor hits FGFR2 and FGFR4 selectively
- F-30 is described as a covalent inhibitor that favors FGFR2 and FGFR4 by reacting with a conserved P-loop cysteine.
- Kinetics show FGFR2 preference over FGFR1 arises mainly in the reversible binding step, not in the inactivation rate.
- Activity is retained against several FGFR2 resistance mutations but weaker against gatekeeper variants; cell effects track FGFR2/4 dependence.
💡 Points
If FGFR2-over-FGFR1 selectivity sits in the reversible Ki rather than kinact, it is a durable, designable handle: affinity can be tuned without chasing reactivity, which matters given the hyperphosphatemia liability of FGFR1 inhibition. Weaker gatekeeper activity is the visible gap, and washout and in vivo target-occupancy data would be the real test of the claim.