Department 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.
Department of Medical Oncology and Sarcoma Center and West German Cancer Center, DKTK partner site Essen, German Cancer Consortium (DKTK), University Duisburg-Essen, Medical School, Essen, Germany.
Nat Commun. 2024 Jan 2;15(1):63. doi: 10.1038/s41467-023-44376-8.
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.
阿伐普利替尼是唯一一种针对 D842V 突变胃肠道间质瘤（GIST）的有效且选择性抑制剂，D842V 突变是血小板衍生生长因子受体α（PDGFRA）最常见的原发性突变。该批准基于 NAVIGATOR 试验，该试验显示总体缓解率超过 90%。尽管有这种变革性的作用，但患者最终还是会进展，主要是由于获得性耐药突变或因神经认知副作用而停药。这些患者没有治疗选择，预后不佳。值得注意的是，对于该药物的结合模式及其药物化学开发知之甚少，而这对于开发下一代药物至关重要。在此背景下，我们解析了阿伐普利替尼与野生型和突变型 PDGFRA 以及干细胞因子受体（KIT）复合物的晶体结构，为抑制剂结合提供了证据和理解，并导致了一个亚口袋（Gα-口袋）的鉴定。我们利用这些信息设计、合成和表征阿伐普利替尼衍生物，以确定克服耐药性和限制潜在血脑屏障穿透的关键药效团特征。
