Marson Charles M
Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London WC1HOAJ, UK.
Anticancer Agents Med Chem. 2009 Jul;9(6):661-92. doi: 10.2174/187152009788679976.
Histone deacetylases (HDACs) remove acetyl groups from the tails of lysine residues of histone protein in nuclear chromatin and also from acetylated sites in non-histone proteins. HDACs and histone acetyltransferases (HATs) are major influences on the level of cellular protein acetylation, and an imbalance in acetylation levels, particularly under-acetylated (hypoacetylated) histone protein has been associated with precancerous or malignant states. Consequently, small molecule inhibitors of HDACs have been synthesised and some now form a newly emerging class of anti-cancer agents that can regulate transcription and inhibit proliferation of cancer cells by inducing cell cycle arrest, differentiation and/or apoptosis, among other major biological phenomena. The different mechanism(s) of action of HDAC inhibitors compared to conventional anti-neoplastic agents provides a possibility that HDAC inhibitors may be effective for refractory cancers. Accordingly, a number of programs for the development of HDAC inhibitors as anti-cancer drugs have been initiated. This review highlights recent developments in the design, synthesis and biological properties of HDAC inhibitors in the context of potential cancer therapy.
组蛋白去乙酰化酶（HDACs）可去除核染色质中组蛋白赖氨酸残基尾部的乙酰基，也能去除非组蛋白蛋白质中乙酰化位点的乙酰基。HDACs和组蛋白乙酰转移酶（HATs）对细胞蛋白质乙酰化水平有主要影响，而乙酰化水平失衡，特别是组蛋白蛋白质乙酰化不足（低乙酰化）与癌前或恶性状态有关。因此，人们合成了HDACs的小分子抑制剂，其中一些现已形成一类新兴的抗癌药物，它们可通过诱导细胞周期停滞、分化和/或凋亡等主要生物学现象来调节转录并抑制癌细胞增殖。与传统抗肿瘤药物相比，HDAC抑制剂不同的作用机制使得其有可能对难治性癌症有效。因此，已经启动了许多将HDAC抑制剂开发为抗癌药物的项目。本综述重点介绍了在潜在癌症治疗背景下HDAC抑制剂在设计、合成和生物学特性方面的最新进展。
