Schulz, Tom2025-02-072025-02-072024http://hdl.handle.net/2003/4344310.17877/DE290R-25274Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract, primarily driven by activating mutations in the receptor tyrosine kinases KIT and PDGFRA. While tyrosine kinase inhibitors (TKIs) have improved treatment outcomes, their efficacy is often compromised by acquired resistance mutations and dose-limiting toxicities. This highlights the need for next-generation inhibitors with improved potency and selectivity. A detailed structural understanding of the kinase's ability to adopt different conformations and the impact of (resistance) mutations is crucial for the development of novel small molecules with improved efficacy. This work elucidates the molecular basis of drug resistance in GIST, focusing on mutations within the ATP-binding pocket and activation loop of the kinase domain. Through in-depth structural analysis and structure-activity relationship (SAR) studies, a previously undescribed, targetable sub-pocket in KIT and PDGFRA was identified. Located between two key regulatory elements, the Gly-rich loop and the αC-helix, this pocket - termed the Gα-pocket - represents a novel target for inhibitor design. These structural insights guided the design and synthesis of novel kinase inhibitors, enabling the identification of key pharmacophoric features necessary to overcome resistance. Given the success of covalent inhibitors such as osimertinib and ibrutinib in the treatment of otherwise drug-resistant cancers, this work explores their untapped potential in GIST to overcome resistance while improving potency and selectivity. In summary, this work lays the foundation for next-generation inhibitors to address the pressing challenge of drug resistance in GIST.enCancerGISTDrug resistanceKinase inhibitorsCovalent inhibitorsStructure-based drug design570540PhDThesisKrebs <Medizin>