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有读书笔记Structure-Activity Relationship Studies of Fostriecin, Cytostatin and Key Analogues, with PP1, PP2A, PP5, and ({beta}12-{beta}13)-chimeras (PP1/PP2A and PP5/PP2A) Provide Further Insight Into Inhibitory Actions of Fostriecin Family Inhibitors

阿平 添加于 2009-7-15 02:38 | 2486 次阅读 | 0 个评论

  •  作 者

    Swingle MS, Amable L, Lawhorn BG, Buck SB, Burke CP, Ratti P, Fischer KL, Boger DL, Honkanen RE

  •  摘 要

    Fostriecin and cytostatin are structurally related natural inhibitors of serine/threonine phosphatases, with promising antitumor activity. The total synthesis of these antitumor agents has enabled the production of structural analogues, which are useful to explore the biological significance of features contained in the parent compounds. Here, the inhibitory activity of fostriecin, cytostatin, and 10 key structural analogues were tested in side-by-side phosphatase assays to further characterize their inhibitory activity against PP1c, PP2Ac, PP5c, and chimeras of PP1 and PP5, in which key residues predicted for inhibitor contact with PP2A were introduced into PP1 and PP5 using site-directed mutagenesis. The data confirms the importance of the C9-phosphate and C11-alcohol for general inhibition and further demonstrates the importance of a predicted C3 interaction with a unique cysteine (C(269)) in the beta12-beta13 loop of PP2A. The data also indicates that additional features beyond the unsaturated lactone contribute to inhibitory potency and selectivity. Notably, a derivative of fostriecin lacking the entire lactone subunit demonstrated marked potency and selectivity for PP2A, while having substantially reduced and similar activity against PP1 and PP1/PP2A- PP5/PP2A-chimeras that have greatly increased sensitivity to both fostriecin and cytostatin. This suggests that other features [e.g. the (Z,Z,E-triene] also contribute to inhibitory selectivity. When considered together with previous data, these studies suggest that despite the high structural conservation of the catalytic site in PP1, PP2A and PP5, the development of highly selective catalytic inhibitors should be feasible.

  •  详细资料

    • 文献种类: Journal Article
    • 期刊名称: The Journal of Pharmacology and Experimental Therapeutics
    • 期刊缩写: J Pharmacol Exp Ther
    • 期卷页: 2009年
    • 地址: University of South Alabama
    • ISBN: 1521-0103
    • 备注:PMID:19592665

  • 学科领域 生物医药 » 生物学

  •  标 签

    PP1  PP2A  PP5  Cytostatin  Fostriecin  药物设计  蛋白结构  小分子抑制剂 

  • 相关链接 DOI URL 

  •  阿平 的文献笔记  订阅

    蛋白磷酸酶研究中常常使用各种小分子抑制剂，但是目前没有一种是真正意义上针对某个蛋白磷酸酶特意的抑制剂。主要还是因为这些酶在进化中都相当保守与接近，很难设计针对性的抑制剂。希望这个研究能给我们设计特异的抑制剂提供一些启发。

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