HDAC7 Inhibition by Phenacetyl and Phenylbenzoyl Hydroxamates,Journal of Medicinal Chemistry

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HDAC7 Inhibition by Phenacetyl and Phenylbenzoyl Hydroxamates
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-02-11 , DOI: 10.1021/acs.jmedchem.0c01967
Jeffrey Y. W. Mak _{1,

2} , Kai-Chen Wu _{1,

2,

3} , Praveer K. Gupta ₄ , Sheila Barbero ₄ , Maddison G. McLaughlin ₄ , Andrew J. Lucke _{1,

2} , Jiahui Tng ₄ , Junxian Lim _{1,

2,

3} , Zhixuan Loh _{1,

2,

3} , Matthew J. Sweet _{2,

3,

5} , Robert C. Reid _{1,

2,

3} , Ligong Liu _{1,

2,

3} , David P. Fairlie _{1,

2,

3,

5}

Affiliation

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 Zn²⁺ 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.

中文翻译：

苯乙酰基和苯基苯甲酰异羟肟酸酯对HDAC7的抑制作用

含锌的组蛋白脱乙酰基酶HDAC7正在成为免疫代谢和癌症的重要调节剂。在这里，我们利用HDAC7中的一个空腔（由HDAC1中的Tyr303填充）来衍生新的抑制剂。苯乙酰基异羟肟酸酯和2-苯基苯甲酰基异羟肟酸酯与Zn ²⁺结合与HDAC1相比，它们是HDAC7选择性抑制剂的50-2700倍。苯甲酰基异羟肟酸酯比苯乙酰基异羟肟酸酯的有效HDAC7抑制剂高30-70倍，这归因于苯甲酰基芳基与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，从而增加抑制剂的效力，肝脏微粒体的稳定性，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产生用于询问与HDAC7催化位点有关的生物学工具。

更新日期：2021-02-25

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