Histone acetylation balance is one epigenetic mechanism controlling gene expression associated with disease progression. It has been observed that histone deacetylase 10 (HDAC-10) isozyme contributes to the chemotherapy resistance; in addition, the poor clinical outcome observed in patients with aggressive solid tumors, such as neuroblastoma, has been associated with its overexpression. Moreover, HDAC-10 selective inhibition suppresses the autophagic response, thus providing an improved risk-benefit profile compared to cytotoxic cancer chemotherapy drugs. On these bases, HDAC-10 is becoming an emerging target for drug design. Due to the rapid progress in the development of next-generation HDAC inhibitors, this review article aims to provide an overview on novel selective or dual HDAC-8/10 inhibitors, as new leads for cancer chemotherapy, able to avoid the severe side-effects of several actual approved "pan" HDAC inhibitors. A literature search was conducted in MedLine, PubMed, Caplus, SciFinder Scholar databases from 2015 to the present. Since the disclosure that the HDAC-6 inhibitor Tubastatin A was able to bind HDAC-10 efficiently, several related analogues were synthesized and tested. Both tricyclic (25-30) and bicyclic (31-42) derivatives were considered. The best pharmacological profile was shown by 36 (HDAC-10 pIC50 = 8.4 and pIC50 towards Class I HDACs from 5.2-6.4). In parallel, based on the evidence that high levels of HDAC-8 are a marker of poor prognosis in neuroblastoma treatment, dual HDAC-8/10 inhibitors were designed. The hydroxamic acid TH34 (HDAC-8 and 10 IC50 = 1.9 μM and 7.7 μM, respectively) and the hybrid derivatives 46d, 46e and 46g were the most promising both in terms of potency and selectivity. Literature surveys indicate several structural requirements for inhibitory potency and selectivity towards HDAC-10, e.g., electrostatic and/or hydrogen bond interactions with E274 and complementarity to the P(E,A) CE motif helix.

中文翻译：

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组蛋白脱乙酰酶 10 (HDAC-10) 的选择性抑制剂。

组蛋白乙酰化平衡是控制与疾病进展相关的基因表达的一种表观遗传机制。已观察到组蛋白脱乙酰酶 10 (HDAC-10) 同工酶有助于化疗耐药；此外，在侵袭性实体瘤（如神经母细胞瘤）患者中观察到的不良临床结果与其过度表达有关。此外，与细胞毒性癌症化疗药物相比，HDAC-10 选择性抑制抑制了自噬反应，从而提供了改善的风险收益特征。在这些基础上，HDAC-10 正在成为药物设计的新兴目标。由于下一代 HDAC 抑制剂的开发进展迅速，这篇综述文章旨在概述新型选择性或双重 HDAC-8/10 抑制剂，作为癌症化疗的新线索，能够避免几种实际批准的“泛”HDAC抑制剂的严重副作用。从 2015 年至今，在 MedLine、PubMed、Caplus、SciFinder Scholar 数据库中进行了文献检索。由于公开了 HDAC-6 抑制剂 Tubastatin A 能够有效地结合 HDAC-10，因此合成并测试了几种相关的类似物。考虑了三环 (25-30) 和双环 (31-42) 衍生物。最好的药理学特征显示为 36（HDAC-10 pIC50 = 8.4 和对 I 类 HDAC 的 pIC50 为 5.2-6.4）。同时，基于证据表明高水平的 HDAC-8 是神经母细胞瘤治疗中预后不良的标志，设计了双重 HDAC-8/10 抑制剂。异羟肟酸 TH34（HDAC-8 和 10 IC50 = 1.9 μM 和 7.7 μM，分别）和杂化衍生物 46d，就效力和选择性而言，46e 和 46g 是最有希望的。文献调查表明对 HDAC-10 的抑制效力和选择性的几个结构要求，例如与 E274 的静电和/或氢键相互作用以及与 P(E,A) CE 基序螺旋的互补性。