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Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA
A Teuber1, T Schulz1, B S Fletcher2
1Department of Chemistry and Chemical Biology, TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW), Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany.
Nature Communications
|January 3, 2024
Summary
Avapritinib treats D842V-mutant gastrointestinal stromal tumors (GIST), but resistance and side effects cause progression. New drug derivatives are designed to overcome resistance and reduce side effects.
Area of Science:
- Oncology
- Structural Biology
- Medicinal Chemistry
Background:
- Avapritinib is a targeted therapy for D842V-mutant gastrointestinal stromal tumors (GIST), a mutation in platelet-derived growth factor receptor alpha (PDGFRA).
- Despite high initial response rates, patients often experience disease progression due to acquired resistance or neuro-cognitive side effects, leaving them with limited therapeutic options.
- Understanding avapritinib's binding mode and medicinal chemistry is crucial for developing next-generation therapies.
Purpose of the Study:
- To elucidate the binding mode of avapritinib to wild-type and mutant PDGFRA and KIT.
- To identify key pharmacophoric features for overcoming drug resistance and mitigating neuro-cognitive side effects.
- To design and synthesize novel avapritinib derivatives.
Main Methods:
- X-ray crystallography was used to determine the structures of avapritinib bound to PDGFRA and KIT.
- Structure-based drug design principles were applied to create avapritinib derivatives.
- Synthesis and characterization of novel compounds were performed.
Main Results:
- Crystal structures revealed avapritinib binding to PDGFRA and KIT, identifying a specific sub-pocket (Gα-pocket).
- Structure-activity relationship studies provided insights into essential pharmacophoric features.
- Novel avapritinib derivatives were synthesized and characterized.
Conclusions:
- Structural insights into avapritinib binding facilitate the development of next-generation inhibitors.
- Targeted modifications can potentially overcome resistance mechanisms in GIST.
- Future research aims to optimize compounds for efficacy and reduced central nervous system toxicity.
