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首页> 外文期刊>Journal of Medicinal Chemistry >HDAC7 Inhibition by Phenacetyl and Phenylbenzoyl Hydroxamates
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HDAC7 Inhibition by Phenacetyl and Phenylbenzoyl Hydroxamates

机译：HDAC7对苯乙炔和苯基苯甲酰基苯甲酸苯甲酰酯的抑制作用

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摘要

The zinc-containing histone deacetylase enzyme HDAC7 is emerging as an important regulator of immunometabolism and cancer. Here, we exploit a cavity in HDAC7, filled by Tyr303 in HDAC1, to derive new inhibitors. Phenacetyl hydroxamates and 2-phenylbenzoyl hydroxamates bind to Zn~(2+) and are 50–2700-fold more selective inhibitors of HDAC7 than HDAC1. Phenylbenzoyl hydroxamates are 30–70-fold more potent HDAC7 inhibitors than phenacetyl hydroxamates, which is attributed to the benzoyl aromatic group interacting with Phe679 and Phe738. Phthalimide capping groups, including a saccharin analogue, decrease rotational freedom and provide hydrogen bond acceptor carbonyl/sulfonamide oxygens that increase inhibitor potency, liver microsome stability, solubility, and cell activity. Despite being the most potent HDAC7 inhibitors to date, they are not selective among class IIa enzymes. These strategies may help to produce tools for interrogating HDAC7 biology related to its catalytic site.
机译：含锌组蛋白去乙酰化酶HDAC7正在成为免疫代谢和癌症的重要调节因子。在这里，我们利用HDAC7中由HDAC1中的Tyr303填充的空腔来衍生新的抑制剂。苯乙酰异羟肟酸盐和2-苯基苯甲酰异羟肟酸盐与Zn~（2+）结合，是HDAC7选择性抑制剂的50-2700倍。苯甲酰异羟肟酸盐是苯乙酰异羟肟酸盐的30-70倍，这归因于苯甲酰芳基与Phe679和Phe738相互作用。邻苯二甲酰亚胺封端基团，包括糖精类似物，会降低旋转自由度，并提供氢键受体羰基/磺酰胺氧，从而提高抑制剂效力、肝微粒体稳定性、溶解度和细胞活性。尽管是迄今为止最有效的HDAC7抑制剂，但它们在IIa类酶中没有选择性。这些策略可能有助于开发工具，用于询问与其催化位点相关的HDAC7生物学。

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  • 来源
    《Journal of Medicinal Chemistry》 |2021年第4期|共19页
  • 作者

    Jeffrey Y. W. Mak; Kai-Chen Wu; Praveer K. Gupta; Sheila Barbero; Maddison G. McLaughlin; Andrew J. Lucke; Jiahui Tng; Junxian Lim; Zhixuan Loh; Matthew J. Sweet; Robert C. Reid; Ligong Liu; David P. Fairlie;

  • 作者单位

    Division of Chemistry and Structural Biology The University of Queensland;

    Division of Chemistry and Structural Biology The University of Queensland;

    Division of Chemistry and Structural Biology Institute for Molecular Bioscience The University of Queensland;

    Division of Chemistry and Structural Biology Institute for Molecular Bioscience The University of Queensland;

    Division of Chemistry and Structural Biology Institute for Molecular Bioscience The University of Queensland;

    Division of Chemistry and Structural Biology The University of Queensland;

    Division of Chemistry and Structural Biology Institute for Molecular Bioscience The University of Queensland;

    Division of Chemistry and Structural Biology The University of Queensland;

    Division of Chemistry and Structural Biology The University of Queensland;

    Australian Research Council Centre of Excellence in Advanced Molecular Imaging Institute for Molecular Bioscience The University of Queensland;

    Division of Chemistry and Structural Biology The University of Queensland;

    Division of Chemistry and Structural Biology The University of Queensland;

    Division of Chemistry and Structural Biology The University of Queensland;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药学;
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