Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents.
Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents.
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DOI：
10.3390/molecules20033898
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发表时间：
2015-03-02
期刊：
影响因子：
--
通讯作者：
Wang G
中科院分区：
文献类型：
--
作者：
Mottamal M;Zheng S;Huang TL;Wang G
组蛋白去乙酰化酶（hdac）是一组从组蛋白中去除乙酰基团并调节肿瘤抑制基因表达的酶。它们与许多人类疾病，特别是癌症有关，通过开发各种抑制剂，使它们成为治疗癌症的有希望的治疗靶点。HDAC抑制剂通过干扰HDAC活性，调节肿瘤细胞的细胞周期、分化和凋亡等生物事件。因此，基于HDAC抑制剂的治疗方法在癌症治疗中得到了广泛的关注。迄今为止，FDA已经批准了三种用于皮肤/外周t细胞淋巴瘤的HDAC抑制剂，还有更多的HDAC抑制剂处于临床开发的不同阶段，用于治疗血液系统恶性肿瘤和实体肿瘤。在不断努力发现新的、希望更有效的HDAC抑制剂的过程中，基于分子模型的合理药物设计在识别分子结构和性质不同的潜在抑制剂方面发挥了重要作用。在这篇综述中，我们总结了处于临床试验中的四种主要结构类型的HDAC抑制剂和不同的计算机建模工具，以发现具有更大治疗效用的其他HDAC抑制剂。
Histone dacetylases (HDACs) are a group of enzymes that remove acetyl groups from histones and regulate expression of tumor suppressor genes. They are implicated in many human diseases, especially cancer, making them a promising therapeutic target for treatment of the latter by developing a wide variety of inhibitors. HDAC inhibitors interfere with HDAC activity and regulate biological events, such as cell cycle, differentiation and apoptosis in cancer cells. As a result, HDAC inhibitor-based therapies have gained much attention for cancer treatment. To date, the FDA has approved three HDAC inhibitors for cutaneous/peripheral T-cell lymphoma and many more HDAC inhibitors are in different stages of clinical development for the treatment of hematological malignancies as well as solid tumors. In the intensifying efforts to discover new, hopefully more therapeutically efficacious HDAC inhibitors, molecular modeling-based rational drug design has played an important role in identifying potential inhibitors that vary in molecular structures and properties. In this review, we summarize four major structural classes of HDAC inhibitors that are in clinical trials and different computer modeling tools available for their structural modifications as a guide to discover additional HDAC inhibitors with greater therapeutic utility.
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