Discovery of Potent FGFR2/3 Inhibitors to Overcome Mutation Resistance and Treat Achondroplasia.

Achondroplasia (ACH), the most prevalent form of human dwarfism, is caused by the G380R mutation in FGFR3 in approximately 99% of cases. Through structural hybridization of Tyra-300 and LY2874455, we developed compound 23, a new dual-target FGFR2/3 inhibitor demonstrating potent activity against both wild-type and mutant FGFR3. In preclinical ACH mouse models, compound 23 showed a dose-dependent improvement in growth rate, with significantly enhanced efficacy versus infigratinib at equivalent doses. This work presents a new structural scaffold for developing FGFR3 kinase inhibitors to target pathogenic FGFR3 mutations and treat ACH.