Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy, University of Groningen A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
Eur J Med Chem. 2012 Jan;47(1):337-44. doi: 10.1016/j.ejmech.2011.11.001. Epub 2011 Nov 10.
Histone acetyltransferases are important enzymes that regulate various cellular functions, such as epigenetic control of DNA transcription. Development of HAT inhibitors with high selectivity and potency will provide powerful mechanistic tools for the elucidation of the biological functions of HATs and may also have pharmacological value for potential new therapies. In this work, analogs of the known HAT inhibitor anacardic acid were synthesized and evaluated for inhibition of HAT activity. Biochemical assays revealed novel anacardic acid analogs that inhibited the human recombinant enzyme Tip60 selectively compared to PCAF and p300. Enzyme kinetics studies demonstrated that inhibition of Tip60 by one such novel anacardic acid derive, 20, was essentially competitive with Ac-CoA and non-competitive with the histone substrate. In addition, these HAT inhibitors effectively inhibited acetyltransferase activity of nuclear extracts on the histone H3 and H4 at micromolar concentrations.
组蛋白乙酰转移酶是一类重要的酶，能够调控多种细胞功能，例如 DNA 转录的表观遗传调控。开发具有高选择性和高活性的 HAT 抑制剂将为阐明 HAT 的生物学功能提供有力的机制工具，并且可能为新型治疗方法提供药理学价值。在这项工作中，我们合成了已知 HAT 抑制剂短叶苏木酚酸的类似物，并对其抑制 HAT 活性的能力进行了评估。生化分析表明，与 PCAF 和 p300 相比，新型短叶苏木酚酸类似物能够选择性地抑制人重组酶 Tip60。酶动力学研究表明，一种新型短叶苏木酚酸衍生物 20 对 Tip60 的抑制作用本质上与 Ac-CoA 呈竞争性，与组蛋白底物呈非竞争性。此外，这些 HAT 抑制剂能够在微摩尔浓度下有效地抑制核提取物中组蛋白 H3 和 H4 的乙酰转移酶活性。
