Orgován Zoltán, Péczka Nikolett, Petri László, Ábrányi-Balogh Péter, Ranđelović Ivan, Tóth Szilárd, Szakács Gergely, Nyíri Kinga, Vértessy Beáta, Pálfy Gyula, Vida István, Perczel András, Tóvári József, Keserű György M
Medicinal Chemistry Research Group, Research Centre for Natural Sciences, and National Drug Discovery and Development Laboratory, Budapest, Hungary.
Medicinal Chemistry Research Group, Research Centre for Natural Sciences, and National Drug Discovery and Development Laboratory, Budapest, Hungary; Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary.
Eur J Med Chem. 2023 Mar 15;250:115212. doi: 10.1016/j.ejmech.2023.115212. Epub 2023 Feb 15.
G12C mutant KRas is considered druggable by allele-specific covalent inhibitors due to the nucleophilic character of the oncogenic mutant cysteine at position 12. Discovery of these inhibitors requires the optimization of both covalent and noncovalent interactions. Here, we report covalent fragment screening of our electrophilic fragment library of diverse non-covalent scaffolds equipped with 40 different electrophilic functionalities to identify fragments as suitable starting points targeting Cys12. Screening the library against KRas using Ellman's free thiol assay, followed by protein NMR and cell viability assays, resulted in two potential inhibitor chemotypes. Characterization of these scaffolds in in vitro cellular- and in vivo xenograft models revealed them as promising starting points for covalent drug discovery programs.
由于致癌突变体半胱氨酸在第12位的亲核特性，G12C突变型KRas被认为可被等位基因特异性共价抑制剂靶向。这些抑制剂的发现需要优化共价和非共价相互作用。在此，我们报告了对我们的亲电片段文库进行共价片段筛选，该文库包含具有40种不同亲电功能的多种非共价支架，以鉴定作为靶向Cys12合适起始点的片段。使用埃尔曼游离硫醇测定法对该文库进行KRas筛选，随后进行蛋白质核磁共振和细胞活力测定，得到了两种潜在的抑制剂化学类型。在体外细胞和体内异种移植模型中对这些支架的表征表明，它们是共价药物发现计划的有前景的起始点。
