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.