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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 | 2487 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:期刊
- 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
标签

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