School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
Curr Med Chem. 2020;27(15):2449-2493. doi: 10.2174/0929867325666181016163110.
Histone Deacetylase (HDAC) inhibitors are a relatively new class of anti-cancer agents that play important roles in epigenetic or non-epigenetic regulation, inducing death, apoptosis, and cell cycle arrest in cancer cells. Recently, their use has been clinically validated in cancer patients resulting in the approval by the FDA of four HDAC inhibitors, vorinostat, romidepsin, belinostat and panobinostat, used for the treatment of cutaneous/peripheral T-cell lymphoma and multiple myeloma. Many more HDAC inhibitors are at different stages of clinical development for the treatment of hematological malignancies as well as solid tumors. Also, clinical trials of several HDAC inhibitors for use as anti-cancer drugs (alone or in combination with other anti-cancer therapeutics) are ongoing. In the intensifying efforts to discover new, hopefully, more therapeutically efficacious HDAC inhibitors, molecular modelingbased rational drug design has played an important role. In this review, we summarize four major structural classes of HDAC inhibitors (hydroxamic acid derivatives, aminobenzamide, cyclic peptide and short-chain fatty acids) 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.
组蛋白去乙酰化酶（HDAC）抑制剂是一类相对较新的抗癌药物，在表观遗传或非表观遗传调控中发挥重要作用，诱导癌细胞死亡、凋亡和细胞周期停滞。最近，它们在癌症患者中的临床应用已经得到验证，美国食品和药物管理局（FDA）批准了四种 HDAC 抑制剂，即伏立诺他、罗米地辛、贝利司他和帕比司他，用于治疗皮肤/外周 T 细胞淋巴瘤和多发性骨髓瘤。还有更多的 HDAC 抑制剂处于治疗血液恶性肿瘤和实体瘤的不同临床开发阶段。此外，正在进行几项 HDAC 抑制剂作为抗癌药物（单独或与其他抗癌疗法联合使用）的临床试验。在发现新的、有希望更具治疗效果的 HDAC 抑制剂的努力中，基于分子建模的合理药物设计发挥了重要作用。在这篇综述中，我们总结了正在临床试验中的四种主要结构类型的 HDAC 抑制剂（羟肟酸衍生物、氨基苯甲酰胺、环肽和短链脂肪酸），以及可用于其结构修饰的不同计算机建模工具，以指导发现具有更大治疗效果的其他 HDAC 抑制剂。
