Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling
Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling
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DOI：
10.1038/nature12205
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发表时间：
2013-05-30
期刊：
影响因子：
64.8
通讯作者：
Waldmann, Herbert
中科院分区：
文献类型：
--
作者：
Zimmermann, Gunther;Papke, Bjoern;Waldmann, Herbert
KRAS癌基因产物被认为是抗癌药物发现的主要靶点（1-3）。然而，直接干扰KRAS信号传导尚未导致临床上有用的药物（3-8）。法尼基化KRAS的正确定位和信号传导由异戊二烯基结合蛋白PDE δ调节，其通过促进KRAS在细胞质中的扩散来维持KRAS的空间组织（9-11）。在这里，我们报告说，通过小分子干扰哺乳动物PDEd与KRAS的结合提供了一个新的机会，通过改变其定位到内膜抑制致癌RAS信号。生物化学筛选和随后的基于结构的命中优化产生了KRAS-PDE δ相互作用的抑制剂，其以纳摩尔亲和力选择性地结合PDE δ的异戊二烯基结合口袋，抑制致癌RAS信号传导并抑制依赖于致癌KRAS的人胰腺导管腺癌细胞的体外和体内增殖。我们的研究结果可能会激发新的药物发现工作，旨在开发针对致癌RAS的药物。
The KRAS oncogene product is considered a major target in anticancer drug discovery(1-3). However, direct interference with KRAS signalling has not yet led to clinically useful drugs(3-8). Correct localization and signalling by farnesylated KRAS is regulated by the prenyl-binding protein PDE delta, which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm(9-11). Here we report that interfering with binding of mammalian PDEd 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-PDE delta interaction that selectively bind to the prenyl-binding pocket of PDE delta 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.