Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors--What Some May Have Forgotten or Would Rather Forget?
Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors--What Some May Have Forgotten or Would Rather Forget?
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DOI：
10.1002/cmdc.201500486
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发表时间：
2016-01-05
期刊：
影响因子：
3.4
通讯作者：
Kozikowski AP
中科院分区：
文献类型：
--
作者：
Shen S;Kozikowski AP
基于羟肟酸盐的组蛋白脱乙酰酶抑制剂（HDACI）已被美国食品和药物管理局批准作为治疗剂用于肿瘤学应用。虽然这种HDAC抑制剂在药物化学的其他领域中的潜在效用是巨大的，但存在显著的担忧，即“泛HDAC抑制剂”对于肿瘤学以外的临床用途可能作用太广和/或毒性太大。除了同工酶选择性挑战外，含异羟肟酸的HDAC抑制剂的潜在致突变性代表了其应用于其他治疗领域的主要障碍。在这里，我们报告已知的异羟肟酸的致突变性，讨论其遗传毒性的机制，并审查目前的一些替代异羟肟酸。我们得出的结论是，异羟肟酸基团虽然提供了高效的HDACI，但不一定是HDACI药物发现的最佳锌结合基团。
Hydroxamate-based histone deacetylase inhibitors (HDACIs) have been approved as therapeutic agents by the US Food and Drug Administration for use in oncology applications. While the potential utility of such HDACIs in other areas of medicinal chemistry is tremendous, there are significant concerns that “pan-HDAC inhibitors” may be too broadly acting and/or toxic for clinical use beyond oncology. In addition to the isozyme selectivity challenge, the potential mutagenicity of hydroxamate-containing HDAC inhibitors represents a major hindrance in their application to other therapeutic areas. Herein we report on the mutagenicity of known hydroxamates, discuss the mechanisms responsible for their genotoxicity, and review some of the current alternatives to hydroxamates. We conclude that the hydroxamate group, while providing high-potency HDACIs, is not necessarily the best zinc-binding group for HDACI drug discovery.