LC-F2-1 is a potent, covalent FGFR2-selective inhibitor with IC50 of 10.0 and 5.8 nM for FGFR2 WT and V565F gatekeeper mutant respectively, has 21-fold selectivity for FGFR1 and >1000-fold for FGFR4 in biochemical assays.
LC-F2-1 demonstrates irreversible covalent binding to FGFR2V565F P-loop residue Cys492 and retains activity against multiple clinically relevant FGFR2 resistance mutations.
LC-F2-1 (1 uM) achieves complete inhibition of FGFR2 including the wild-type (WT) and the N550H, R612T, K526E, and K660N mutants, also exhibits robust inhibitory activity (>90% inhibition) against several other FGFR2 mutants, including E566G, K642R, V565I, and V565F.
LC-F2-1 shows limited off-target effect (>80% inhibition aty 1 uM) against panel of 416 human kinases.
LC-F2-1 demonstrates potent inhibition with IC50 of 4.0 nM Ba/F3 cell models expressing FGFR2, FGFR1- and FGFR3-expressing cells exhibits markedly reduced responsiveness, with 44-fold (IC50=175.9 nM) and 23-fold (IC50=93.4 nM) lower selectivity, respectively.
LC-F2-1 potently inhibits FGFR2 downstream signaling, inhibits pFGFR and pERK in gastric cancer cell line KATOIII with a potency of 4.7 nM and 12.0 nM, respectively.
LC-F2-1 (20-100 nM) significantly attenuates the phosphorylation of critical FGFR2 signaling components in both KATOIII and SNU-16 cellular models.
LC-F2-1 demonstrates a 9.4-fold potency shift against FGFR2 N550K-expressing Ba/F3 cells (IC50=37.6 nM) compared to that against FGFR2WT.
LC-F2-1 (10 mg/kg) overcomes FGFR2 V565F/M538I mutations in xenograft model using FGFR2V565F-Ba/F3 cells.