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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.

DOI PubMed

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At this year's Frontiers in Medicinal Chemistry meeting in Vienna, organized by the German Chemical Society (GDCh), Tonia Kirschner from the Rauh group was honored with an award for her poster presentation.

Ms. Kirschner presented her results on novel covalent inhibitors for the KRas G13C mutant, which is relevant in cancer development and remains largely unexplored. Within their previous PhD work, structure-based drug design was used to obtain small molecule compounds that bind for the first time into the allosteric switch-II pocket of KRas G13C and react covalently with the cysteine residue.

The annual international symposium provides exchange for academia and industry on recent developments, new approaches and cutting-edge technologies in the field of medicinal chemistry and drug discovery.

Impressions from the FORTRESS meeting 2023!