Mercaptoacetamide: A promising zinc-binding group for the discovery of selective histone deacetylase 6 inhibitors.
Mercaptoacetamide: A promising zinc-binding group for the discovery of selective histone deacetylase 6 inhibitors.
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默皮乙酰胺：一种有前途的锌结合基，用于发现选择性组蛋白脱乙酰基酶6抑制剂。
DOI：
10.1016/j.ejmech.2020.112887
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发表时间：
2021-01-01
影响因子：
6.7
通讯作者：
Shen S
中科院分区：
文献类型：
--
作者：
Tavares MT;Kozikowski AP;Shen S
组蛋白去乙酰化酶6（HDAC 6）是一种锌依赖性HDAC，主要调节非组蛋白底物如α-微管蛋白和热休克蛋白90（HSP 90）的乙酰化状态。HDAC 6的活性在细胞增殖、蛋白质运输和降解、细胞形状、迁移以及免疫调节因子的调节中起关键作用。因此，HDAC 6影响癌症、神经退行性疾病和自身免疫反应的进展。在过去的几年中，选择性HDAC 6抑制剂（HDAC 6 is）的发现已经成为一个有吸引力的研究领域，因为五个HDAC 6 is正在I/II期临床试验中进行研究。然而，异羟肟酸官能团仍然代表主要的锌结合基团（ZBG），其通常遭受不良的药代动力学和致突变潜力，从而损害基于异羟肟酸的HDAC 6 is用于长期治疗的应用。另一方面，基于巯基乙酰胺（MCA）的HDAC 6由一类化合物组成，在某些情况下，这些化合物显示出纳摩尔HDAC 6效力和比I类HDAC同工酶高出一千倍的选择性。此外，基于MCA的HDAC 6 is缺乏与异羟肟酸功能相关的致突变性并显示药理学作用，证明了这种特定ZBG改善HDAC 6 is的药物样性质的潜力。在此，我们首次总结了基于MCA的HDAC 6 is的结构-活性关系（SAR），讨论了其HDAC 6选择性在分子水平上使用的cadheror-HDAC共晶体结构，并进一步提供我们的观点，关于他们的药物代谢，药代动力学和药理学性质。
Histone deacetylase 6 (HDAC6) is a zinc-dependent HDAC that mainly modulates the acetylation status of non-histone substrates, such as α-tubulin and heat shock protein 90 (HSP90). The activity of HDAC6 plays a critical role in cell proliferation, protein trafficking and degradation, cell shape, migration, as well as regulation of immunomodulatory factors. For this reason, HDAC6 influences the progress of cancers, neurodegenerative disorders, and autoimmune responses. In the last few years, the discovery of selective HDAC6 inhibitors (HDAC6is) has become an attractive research area as five HDAC6is are being investigated in phase I/II clinical trials. However, the hydroxamic acid functional group still represents the predominant zinc-binding group (ZBG), that often suffers from poor pharmacokinetics and mutagenic potential, thus impairing the application of hydroxamate-based HDAC6is for long-term therapies. On the other hand, mercaptoacetamide (MCA)-based HDAC6is comprise a class of compounds that, in some cases, display nanomolar HDAC6 potency and a thousand-fold selectivity over class I HDAC isozymes. Moreover, MCA-based HDAC6is lack the mutagenicity associated with the hydroxamate function and display pharmacological effects, demonstrating the potential of this particular ZBG to improve upon the drug-like properties of HDAC6is. Herein, we summarize for the first time the structure-activity relationships (SARs) of MCA-based HDAC6is, discuss their HDAC6 selectivity at the molecular level using inhibitor-HDAC co-crystal structures, and further provide our perspective regarding their drug metabolism, pharmacokinetics, and pharmacological properties.
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