News & Events
Lecture Series - Modern Drug Discovery - SoSe 2024
The agenda for our upcoming Lecture Series on "Modern Drug Discovery" is there!
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Neue Einblicke in die Resistenzmechanismen eines seltenen Tumors
Wie lassen sich gastrointestinale Stromatumoren – kurz GIST – behandeln und neue Therapien entwickeln? Diesen Fragen gehen die Arbeitsgruppen von Prof. Daniel Rauh von der Fakultät für Chemie und Chemische Biologie an der TU Dortmund und Prof. Sebastian Bauer vom Westdeutschen Tumorzentrum am Universitätsklinikum Essen gemeinsam nach. Seit mehr als zehn Jahren forschen die Wissenschaftler*innen der Essener Onkologie und der Dortmunder Wirkstoffforschung zu GIST. Jetzt konnten sie gemeinsam neue Einblicke in die molekularen Mechanismen hinter den Resistenzmutationen dieses seltenen Magen/Darm-Krebs gewinnen: Die Erkenntnisse wurden in „Nature Communications“ und im „Journal of Clinical Oncology“ veröffentlicht.
Novel binding pocket in KIT and PDGFRA discovered
The study, "Avapritinib-based SAR Studies Unveil a Binding Pocket in KIT and PDGFRA," published in Nature Communications, represents a collaborative milestone achieved by researchers from the Drug Discovery Hub Dortmund (DDHD) and physicians from the West German Tumor Center in Essen (WTZ). This interdisciplinary effort has successfully elucidated the molecular structures of key cancer proteins.
Avapritinib is the only potent and selective inhibitor approved for the treatment of D842V-mutant gastrointestinal stromal tumors (GIST), the most common primary mutation of the platelet-derived growth factor receptor α (PDGFRA). The approval was based on the NAVIGATOR trial, which revealed overall response rates of more than 90%. Despite this transformational activity, patients eventually progress, mostly due to acquired resistance mutations or following discontinuation due to neuro-cognitive side effects. These patients have no therapeutic alternative and face a dismal prognosis. Notable, little is known about this drug's binding mode and its medicinal chemistry development, which is instrumental for the development of the next generation of drugs. Against this background, we solve the crystal structures of avapritinib in complex with wild-type and mutant PDGFRA and stem cell factor receptor (KIT), which provide evidence and understanding of inhibitor binding and lead to the identification of a sub-pocket (Gα-pocket). We utilize this information to design, synthesize and characterize avapritinib derivatives for the determination of key pharmacophoric features to overcome drug resistance and limit potential blood-brain barrier penetration.