2. Academic Validation
  3. Design, Synthesis, and SAR of Covalent KIT and PDGFRA Inhibitors─Exploring Their Potential in Targeting GIST

Design, Synthesis, and SAR of Covalent KIT and PDGFRA Inhibitors─Exploring Their Potential in Targeting GIST

  • J Med Chem. 2025 Feb 13;68(3):3238-3259. doi: 10.1021/acs.jmedchem.4c02472.
Tom Schulz 1,  Rajesh Gontla 1,  Alina Teuber 1,  Maria Beerbaum 1,  Benjamin S Fletcher 2,  Thomas Mühlenberg 2,  Helena Kaitsiotou 1,  Julia Hardick 1,  Kirujan Jeyakumar 1,  Marina Keul 1,  Matthias P Müller 1,  Sonja Sievers 3,  Sebastian Bauer 2,  Daniel Rauh 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Chemical Biology, TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW), Otto-Hahn-Strasse 4a, Dortmund 44227, Germany.
  • 2 Department of Medical Oncology and Sarcoma Center, West German Cancer Center, and DKTK partner site Essen, German Cancer Consortium (DKTK), University Duisburg-Essen, Medical School, Hufelandstraße 55, Essen 45122, Germany.
  • 3 Max Planck Institute of Molecular Physiology, Compound Management and Screening Center (COMAS), Otto-Hahn-Straße 11, Dortmund 44227, Germany.
PMID: 39841084 DOI: 10.1021/acs.jmedchem.4c02472
Abstract

Gastrointestinal stromal tumors (GIST), driven by KIT and PDGFRA mutations, are the most common mesenchymal tumors of the gastrointestinal tract. Although tyrosine kinase inhibitors (TKIs) have advanced treatment, resistance mutations and off-target toxicity limit their efficacy. This study develops covalent TKIs targeting drug-resistant GIST through structure-based design, synthesis, and biological evaluation. SAR studies provided key insights into mutant KIT and PDGFRA interactions, and the first crystal structure of PDGFRA bound to a covalent inhibitor is reported. These findings highlight the promise of covalent inhibitors for overcoming resistance and advancing safer, more effective therapies for advanced GIST.

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