Histone deacetylase inhibitors.
Histone deacetylase inhibitors.
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DOI：
10.1002/chin.200519250
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发表时间：
2005-05
影响因子：
6.7
通讯作者：
C. Monneret
中科院分区：
文献类型：
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作者：
C. Monneret
组蛋白是一种小的碱性蛋白质，通过与DNA复合，形成核小体核心。这种核小体的重复单位导致了染色质，所有人类基因组都被包装在染色质中。组蛋白可以是两种拮抗剂形式之一，乙酰化或脱乙酰化，由相应的酶，组蛋白乙酰化酶和组蛋白脱乙酰酶（HDAC）调节平衡。HDAC的抑制代表了人类癌症治疗中的新策略，因为这些酶在调节基因表达和染色质组装中起着重要作用。它们是肿瘤细胞生长停滞、分化和凋亡的有效诱导剂。已经报道了多种天然和合成来源的HDAC。除了缩肽FK 228之外，天然HDAC（阿司他汀（TSA）、depudecin、trapoxins、apicidins）以及丁酸钠、苯丁酸和辛二酰苯胺异羟肟酸（SAHA）虽然在体内有效，但由于不稳定和低保留而效率低下。随后，发现从筛选文库中分离的合成类似物（oxamflatin，scriptaid）与TSA和SAHA具有共同的结构：通过间隔基（5或6个CH 2）连接至疏水基团的异羟肟酸锌结合基团。第二代HDAC的设计是基于这些数据，这些数据提供了目前处于I期临床试验的有效HDAC，如LAQ 824和PDX 101。同时，合成的含苯甲酰胺的HDAC被报道，其中两种，MS-275和CI-994，已分别达到II期和I期临床试验。
Histones are small basic proteins that, by complexing wtih DNA, form the nucleosome core. Repetitive units of this nucleosome led to the chromatin in which all the human genome is packaged. Histones can be in one of the two antagonist forms, acetylated or deacetylated, equilibrium regulated by the corresponding enzymes, histone acetylases and histones deacetylases (HDACs). Inhibition of HDACs represents a new strategy in human cancer therapy since these enzymes play a fundamental role in regulating gene expression and chromatin assembly. They are potent inducers of growth arrest, differentiation and apoptosis of tumor cells. A wide variety of HDACs of both natural and synthetic origin has been reported. Except depsispeptide FK228, natural HDACs (trichostatin (TSA), depudecin, trapoxins, apicidins) as well as sodium butyrate, phenylbutyrate and suberoyl anilide hydroxamic acid (SAHA), while effective in vivo, are inefficient due to instability and low retention. Subsequently, synthetic analogs isolated from screening libraries (oxamflatin, scriptaid) were discovered as havind a common structure with TSA and SAHA: an hydroxamic acid zinc-binding group linked via a spacer (5 or 6 CH2) to a hydrophobic group. Design of a second generation of HDACs was based upon these data affording potent HDACs such as LAQ824 and PDX101 currently under phase I clinical trials. Simultaneously, synthetic benzamide-containing HDACs were reported and two of them, MS-275 and CI-994, have reached phase II and I clinical trials, respectively.