Perspective: how structure-guided design finally delivered FGFR3-selective inhibitors
- Second-generation pan-FGFR inhibitors proved the concept but were limited by toxicities from inhibiting FGFR1, FGFR2 and FGFR4.
- Despite high structural homology across the family, structure-guided work has produced the first FGFR3-selective inhibitors to reach clinical evaluation.
- The Perspective covers the biological rationale, the design strategies behind the selectivity and emerging indications, including bladder cancer and achondroplasia.
💡 Points
Isoform selectivity inside a highly conserved kinase family is a good test of how far structure-based design really goes, and FGFR3 now has clinical-stage answers. The achondroplasia angle is the interesting one: a chronic, pediatric-adjacent indication raises the tolerability bar far above oncology, which is exactly where selectivity pays off.