Rational Design and Identification of ISM7594 as a Tissue-Agnostic FGFR2/3 Inhibitor

The selective inhibition of fibroblast growth factor receptors (FGFR) presents a significant challenge due to the high degree of sequence and the close structural similarity of the subtypes. Herein, we designed selective dual FGFR2/3 inhibitors based on the in-depth understanding of protein-ligand interaction contributions. We efficiently identified ISM7594 (4) with distinctive flexible hinge binder and a unique central core that potently inhibited FGFR2/3 and selectively spared FGFR1/4. The "magic methyl" effect played a crucial role in enhancing the activity. ISM7594 maintained strong activity against multiple FGFR2/3 mutants known to drive resistance to current drugs and broad-spectrum antiproliferative potency in cancer cells harboring diverse FGFR2/3 alterations, including FGFR2/3 amplification, fusion, and mutation types. The compound demonstrated robust tumor growth suppression, favorable pharmacokinetic profile, and pharmacodynamic effects. This study supports the preclinical development of ISM7594 and demonstrates its potential in advancing tissue-agnostic therapy for advanced solid tumors with FGFR2/3 aberrations and mutation resistance.