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Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling

机译：小分子抑制KRAS-PDEδ相互作用削弱致癌性KRAS信号传导

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摘要

The KRAS oncogene product is considered a major target in anti-cancer drug discovery. However, direct interference with KRAS signalling has not yet led to clinically useful drugs. Correct localization and signalling by farnesylated KRAS is regulated by the prenyl-binding protein PDE5, which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm. Here we report that interfering with binding of mammalian PDE8 to KRAS by means of small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDE5 interaction that selectively bind to the prenyl-binding pocket of PDE6 with nanomolar affinity, inhibit oncogenic RAS signalling and suppress in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. Our findings may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic RAS.
机译：KRAS癌基因产品被认为是抗癌药物发现的主要目标。然而，对KRAS信号的直接干扰尚未导致临床上有用的药物。法呢基化的KRAS的正确定位和信号传导受异戊二烯结合蛋白PDE5调控，异戊二烯结合蛋白PDE5通过促进KRAS在细胞质中的扩散来维持KRAS的空间组织。在这里我们报告说，通过小分子干扰哺乳动物PDE8与KRAS的结合，提供了一个新的机会，即通过改变其对内膜的定位来抑制致癌RAS信号传导。生化筛选和随后的基于结构的命中优化产生了KRAS-PDE5相互作用的抑制剂，该抑制剂以纳摩尔亲和力选择性结合PDE6的异戊二烯结合口袋，抑制致癌RAS信号传导并抑制人胰腺导管腺癌细胞的体外和体内增殖。取决于致癌的KRAS。我们的发现可能会激发旨在开发针对致癌RAS的药物的新型药物发现方法。

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  • 来源
    《Nature》 |2013年第7451期|638-642|共5页
  • 作者

    Gunther Zimmermann; Bjoern Papke; Shehab Ismail; Nachiket Vartak; Anchal Chandra; Maike Hoffmann; Stephan A. Hahn; Gemma Triola; Alfred Wittinghofer; Philippe I. H. Bastiaens; Herbert Waldmann;

  • 作者单位

    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany;

    Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology,D-44227 Dortmund, Germany;

    Structural Biology Group, Max Planck Institute for Molecular Physiology, D-44227 Dortmund, Germany;

    Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology,D-44227 Dortmund, Germany;

    Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology,D-44227 Dortmund, Germany;

    Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, D-44801 Bochum, Germany;

    Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, D-44801 Bochum, Germany;

    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany;

    Structural Biology Group, Max Planck Institute for Molecular Physiology, D-44227 Dortmund, Germany;

    Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology,D-44227 Dortmund, Germany,Chemical Biology, Faculty of Chemistry, TU Dortmund, D-44227 Dortmund, Germany;

    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany,Chemical Biology, Faculty of Chemistry, TU Dortmund, D-44227 Dortmund, Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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