FGFR2-FGFR4 inhibitor F-30 is a potent, selective covalent inhibitor of FGFR2/4 with IC50 of 7.8 nM and 11 nM for FGFR2 and FGFR4 respectively.
F-30 shows much weaker activity against FGFR1 and FGFR3 with IC50 of 315 nM and 91 nM respectively.
F-30 exhibits a KI value of 4.6 nM for FGFR2, which was approximately 12-fold lower than that for FGFR1 (53 nM).
F-30 strongly suppresses the proliferation of Ba/F3 cells driven by FGFR2 or FGFR4, with IC50 values of 5.9 nM and 19 nM, respectively, with substantially reduced in FGFR1- and FGFR3-driven models (IC50=456 nM and 76 nM).
Cys477 is critical for the potent covalent inhibition of FGFR4 by F-30, and F-30 shows covalent binding to FGFR2 at Cys491.
F-30 retains potent activity against multiple clinically relevant FGFR2 mutations N549K/H/D, E565A, K641R, potently inhibits all tested mutant variants with IC50 values in the low nanomolar range.
F-30 is less effective against gatekeeper mutations.
F-30 inhibits the proliferation of FGFR-driven cancer cell lines and suppresses FGFR-mediated signaling pathways.