FGFR2/3-IN-3 is a dual-target FGFR2/3 inhibitor with IC50 values of 2.7 nM (TEL-FGFR2) and 3.9 nM (TEL-FGFR3), displaying efficacy against both wild-type and mutant FGFR3. It exhibits low CYP3A4 inhibition and minimal hERG toxicity. By inhibiting mutant FGFR3-mediated pathways, FGFR2/3-IN-3 improves chondrocyte proliferation and differentiation imbalances, promoting bone growth. In a dwarfism mouse model, it demonstrates growth-promoting effects, indicating potential for treating bone development disorders such as achondroplasia (ACH).

CYP2C9:3.9 μM

FGFR2/3-IN-3 (compound 23) exhibits potent inhibitory activity against FGFR3 wild-type (IC50 = 3.2 nM) and V555M mutant (IC50 = 0.5 nM), as well as TEL-FGFR1 (IC50 = 29.4 nM) and TEL-FGFR4 (IC50 = 29 nM). It also demonstrates inhibition in the TEL-FGFR3 mutant Ba/F3 cell line with common mutations such as FGFR3G380R (IC50 = 7.0 nM), FGFR3WT (IC50 = 3.9 nM), FGFR3V555L (IC50 = 1.7 nM), and FGFR3L608V (IC50 = 10.0 nM) ACH. The compound inhibits the growth of RT-112/84 cells in FGFR3-driven tumor cells (IC50 = 1.3 nM). FGFR2/3-IN-3 shows slightly stronger inhibition on CYP subtypes 2C9 (IC50 = 3.9 μM) and 2D6 (IC50 = 5.0 μM) compared to subtype 3A4. Additionally, FGFR2/3-IN-3 (at concentrations of 0.2 μM and 1 μM) can rescue growth retardation in an FGF-induced mouse ex vivo femur culture model.

FGFR2/3-IN-3, administered subcutaneously at doses of 0.5 mg/kg and 2 mg/kg for 14 days, enhances overall growth in Fgfr3 Y367C/+ mouse models of ACH and stimulates the growth of the tail, tibia, and femur.