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首页> 外文期刊>Chemistry: A European journal >A Guanidyl-Based Bivalent Peptidomimetic Inhibits K-Ras Prenylation and Association with c-Raf
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A Guanidyl-Based Bivalent Peptidomimetic Inhibits K-Ras Prenylation and Association with c-Raf

机译：基于胍基的二价肽染色体抑制K-RAS戊基化和与C-RAF的关联

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摘要

Unusual lipid modification of K-Ras makes Ras-directed cancer therapy a challenging task. Aiming to disrupt electrostatic-driven protein-protein interactions (PPIs) of KRas with FTase and GGTase I, a series of bivalent dual inhibitors that recognize the active pocket and the common acidic surface of FTase and GGTaseI were designed. The structure-activity-relationship study resulted in 8b, in which a biphenyl-based peptidomimetic FTI-277 was attached to a guanidyl-containing gallate moiety through an alkyl linker. Cell-based evaluation demonstrated that 8b exhibited substantial inhibition of K-Ras processing without apparent interference with Rap-1A processing. Fluorescent imaging showed that 8b disrupts localization of K-Ras to the plasma membrane and impairs interaction with c-Raf, whereas only FTI-277 was found to be inactive. These results suggest that targeting the PPI interface of K-Ras may provide an alternative method of inhibiting K-Ras.
机译：K-Ras的异常脂质改性使RAS导向的癌症治疗成为一个具有挑战性的任务。 旨在破坏用FTase和GGTase I破坏KRA的静电驱动的蛋白质 - 蛋白质相互作用（PPI），设计了一系列识别活性口袋和FTase和GGTasei的常见酸性表面的一系列二价双抑制剂。 结构 - 活性关系研究导致8B，其中通过烷基接头将基于联苯基的肽瘤FTI-277连接到含胍基吲哚酯部分。 基于细胞的评估表明，8B表现出大量抑制K-RAS加工，而无明显干扰RAP-1A加工。 荧光成像表明，8B破坏k-ras对血浆膜的定位，损害与c-raf的相互作用，而仅发现FTI-277是无活性的。 这些结果表明，靶向K-RA的PPI界面可以提供抑制K-RA的替代方法。

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  • 来源
    《Chemistry: A European journal》 |2019年第59期|共6页
  • 作者

    Mai Tsubamoto; Toan Khanh Le; Minghua Li; Taku Watanabe; Chiemi Matsumi; Prakash Parvatkar; Hiroshi Fujii; Nobuo Kato; Jiazhi Sun; Junko Ohkanda;

  • 作者单位

    The Institute of Scientific Industrial Research Osaka University 8-1 Mihogaoka Ibaraki Osaka 567-0047 (Japan);

    Academic Assembly Institute of Agriculture Shinshu University 8304 Minami-Minowa Kami-Ina Nagano 399-4598 (Japan);

    Department of Pharmaceutical Science University of South Florida Tampa Florida 33612 (USA);

    Ina Laboratory Medical &

    Biological Laboratories CO. Ltd. Ina Nagano 396-0002 (Japan);

    Ina Laboratory Medical &

    Biological Laboratories CO. Ltd. Ina Nagano 396-0002 (Japan);

    Institute for Chemical Research Kyoto University Gokasho Uji Kyoto 611-0011 (Japan);

    Academic Assembly Institute of Agriculture Shinshu University 8304 Minami-Minowa Kami-Ina Nagano 399-4598 (Japan);

    The Institute of Scientific Industrial Research Osaka University 8-1 Mihogaoka Ibaraki Osaka 567-0047 (Japan);

    Department of Pharmaceutical Science University of South Florida Tampa Florida 33612 (USA);

    Academic Assembly Institute of Agriculture Shinshu University 8304 Minami-Minowa Kami-Ina Nagano 399-4598 (Japan);

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 应用化学;
  • 关键词

    bivalent inhibitors; c-Raf; K-Ras; prenylation; protein-protein interactions;

    机译：二价抑制剂;C-RAF;K-Ras;戊基化;蛋白质 - 蛋白质相互作用;

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