Pimelic Diphenylamide 106 Is a Slow, Tight-binding Inhibitor of Class I Histone Deacetylases
Pimelic Diphenylamide 106 Is a Slow, Tight-binding Inhibitor of Class I Histone Deacetylases
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DOI：
10.1074/jbc.m807045200
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发表时间：
2008-12-19
影响因子：
4.8
通讯作者：
Gottesfeld, Joel M.
中科院分区：
文献类型：
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作者：
Chou, C. James;Herman, David;Gottesfeld, Joel M.
组蛋白脱乙酰酶（HDAC）抑制剂，包括各种苯甲酰胺和异羟肟酸盐，目前正处于用于广泛的人类疾病（包括癌症和神经退行性疾病）的临床开发中。我们最近报道了一个家庭的苯甲酰胺型HDAC抑制剂，是相对无毒的异羟肟酸相比，鉴定。这类化合物的成员已经在神经变性疾病弗里德赖希共济失调和亨廷顿病的基于细胞的模型和小鼠模型中显示出功效。对于许多HDAC抑制剂，已经报道了各种HDAC酶的IC 50值的相当大的差异，导致这些化合物的HDAC同种型特异性的混淆。在这里，我们表明苯甲酰胺HDAC抑制剂，庚二二苯酰胺（106），是一种I类HDAC抑制剂，对II类HDAC没有活性。106是HDAC 1、2和3的缓慢、紧密结合的抑制剂，尽管对这些酶的抑制通过不同的机制发生。抑制剂106还具有对HDAC 3的偏好，Ki类似于14 nM，比HDAC 1的Ki低15倍。相比之下，异羟肟酸辛二酰苯胺异羟肟酸并不区分这些酶，并表现出一个快速/快速关闭抑制机制。这些观察结果可以解释一个悖论，涉及庚二酰二苯酰胺与异羟肟酸作为基因激活剂的相对活性。
Histone deacetylase (HDAC) inhibitors, including various benzamides and hydroxamates, are currently in clinical development for a broad range of human diseases, including cancer and neurodegenerative diseases. We recently reported the identification of a family of benzamide-type HDAC inhibitors that are relatively non-toxic compared with the hydroxamates. Members of this class of compounds have shown efficacy in cell-based and mouse models for the neurodegenerative diseases Friedreich ataxia and Huntington disease. Considerable differences in IC50 values for the various HDAC enzymes have been reported for many of the HDAC inhibitors, leading to confusion as to the HDAC isotype specificities of these compounds. Here we show that a benzamide HDAC inhibitor, a pimelic diphenylamide (106), is a class I HDAC inhibitor, demonstrating no activity against class II HDACs. 106 is a slow, tight-binding inhibitor of HDACs 1, 2, and 3, although inhibition for these enzymes occurs through different mechanisms. Inhibitor 106 also has preference toward HDAC3 with K-i of similar to 14 nM, 15 times lower than the Ki for HDAC1. In comparison, the hydroxamate suberoylanilide hydroxamic acid does not discriminate between these enzymes and exhibits a fast-on/fast-off inhibitory mechanism. These observations may explain a paradox involving the relative activities of pimelic diphenylamides versus hydroxamates as gene activators.