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Related Experiment Video

Updated: Sep 18, 2025

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

Yazhou Wang1, Jinxin Liu1, Yihong Zhang1

  • 1Insilico Medicine Shanghai Ltd, Suite 901 Tower C, Changtai Plaza, 2889 Jinke Road, Pudong New District, Shanghai 201203, China.

Journal of Medicinal Chemistry
|June 25, 2025
PubMed
Summary

Researchers developed ISM7594, a selective dual inhibitor targeting fibroblast growth factor receptors (FGFR) 2 and 3. This novel compound shows potent activity against FGFR2/3 alterations and resistance mutations, offering potential for advanced solid tumor therapies.

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Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Pharmacology

Background:

  • Selective inhibition of fibroblast growth factor receptors (FGFR) is challenging due to subtype similarity.
  • FGFR2 and FGFR3 alterations drive various advanced solid tumors.
  • Drug resistance often arises from FGFR mutations.

Purpose of the Study:

  • To design selective dual FGFR2/3 inhibitors.
  • To identify novel compounds overcoming resistance mechanisms.
  • To evaluate preclinical efficacy for advanced solid tumors.

Main Methods:

  • Structure-based drug design focusing on protein-ligand interactions.
  • Development of a flexible hinge binder and unique central core.
  • In vitro and in vivo testing of compound ISM7594 against FGFR2/3 and resistant mutants.

Main Results:

  • ISM7594 selectively inhibits FGFR2/3 while sparing FGFR1/4.
  • The compound demonstrates potent activity against FGFR2/3 alterations (amplification, fusion, mutation) and resistance mutations.
  • ISM7594 exhibits broad-spectrum antiproliferative effects, robust tumor growth suppression, and favorable pharmacokinetics.

Conclusions:

  • ISM7594 is a potent and selective dual FGFR2/3 inhibitor with activity against resistant mutants.
  • The compound shows promise for treating advanced solid tumors with FGFR2/3 aberrations.
  • Preclinical development of ISM7594 is supported, highlighting its potential in tissue-agnostic therapy.