Division of Chemistry and Structural Biology, The University of Queensland, Brisbane, Queensland 4072, Australia.
Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
J Med Chem. 2021 Feb 25;64(4):2186-2204. doi: 10.1021/acs.jmedchem.0c01967. Epub 2021 Feb 11.
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 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.
含锌的组蛋白去乙酰化酶 HDAC7 作为免疫代谢和癌症的重要调节剂正在兴起。在这里，我们利用 HDAC7 中的一个空腔，该空腔由 HDAC1 中的 Tyr303 填充，从而衍生出新的抑制剂。苯乙酰基羟肟酸和 2-苯甲酰基羟肟酸与 Zn 结合，对 HDAC7 的选择性比 HDAC1 高 50-2700 倍。苯甲酰基羟肟酸对 HDAC7 的抑制作用比苯乙酰基羟肟酸强 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，可降低旋转自由度，并提供氢键受体羰基/磺酰胺氧基，从而提高抑制剂的效力、肝微粒体稳定性、溶解度和细胞活性。尽管它们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研究与 HDAC7 催化位点相关的生物学的工具。
