Wang Yuren, Wallach Jason, Duane Stephanie, Wang Yuan, Wu Jianghong, Wang Jeffrey, Adejare Adeboye, Ma Haiching
Reaction Biology Corp., Malvern.
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA, USA.
Drug Des Devel Ther. 2017 May 2;11:1369-1382. doi: 10.2147/DDDT.S124977. eCollection 2017.
Histone deacetylases (HDACs) are key regulators of gene expression in cells and have been investigated as important therapeutic targets for cancer and other diseases. Different subtypes of HDACs appear to play disparate roles in the cells and are associated with specific diseases. Therefore, substantial effort has been made to develop subtype-selective HDAC inhibitors. In an effort to discover existing scaffolds with HDAC inhibitory activity, we screened a drug library approved by the US Food and Drug Administration and a National Institutes of Health Clinical Collection compound library in HDAC enzymatic assays. Ebselen, a clinical safe compound, was identified as a weak inhibitor of several HDACs, including HDAC1, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, and HDAC9 with half maximal inhibitory concentrations approximately single digit of µM. Two ebselen analogs, ebselen oxide and ebsulfur (a diselenide analog of ebselen), also inhibited these HDACs, however with improved potencies on HDAC8. Benzisothiazol, the core structure of ebsulfur, specifically inhibited HDAC6 at a single digit of µM but had no inhibition on other HDACs. Further efforts on structure-activity relationship based on the core structure of ebsulfur led to the discovery of a novel class of potent and selective HDAC6 inhibitors with RBC-2008 as the lead compound with single-digit nM potency. This class of histone deacetylase inhibitor features a novel pharmacophore with an ebsulfur scaffold selectively targeting HDAC6. Consistent with its inhibition on HDAC6, RBC-2008 significantly increased the acetylation levels of α-tubulin in PC-3 cells. Furthermore, treatment with these compounds led to cell death of multiple tumor cell lines in a dose-dependent manner. These results demonstrated that ebselen and ebsulfur analogs are inhibitors of HDACs, supporting further preclinical development of this class of compounds for potential therapeutic applications.
组蛋白去乙酰化酶（HDACs）是细胞中基因表达的关键调节因子，已被作为癌症和其他疾病的重要治疗靶点进行研究。不同亚型的HDACs在细胞中似乎发挥着不同的作用，并与特定疾病相关。因此，人们付出了巨大努力来开发亚型选择性HDAC抑制剂。为了发现具有HDAC抑制活性的现有骨架，我们在美国食品药品监督管理局批准的药物库和美国国立卫生研究院临床化合物库中进行了HDAC酶活性测定筛选。依布硒仑是一种临床安全的化合物，被鉴定为几种HDACs的弱抑制剂，包括HDAC1、HDAC3、HDAC4、HDAC5、HDAC6、HDAC7、HDAC8和HDAC9，其半数最大抑制浓度约为个位数的微摩尔。两种依布硒仑类似物，氧化依布硒仑和依布硫（依布硒仑的二硒化物类似物），也抑制这些HDACs，但对HDAC8的效力有所提高。依布硫的核心结构苯并异噻唑在个位数的微摩尔浓度下特异性抑制HDAC6，但对其他HDACs没有抑制作用。基于依布硫的核心结构进一步开展构效关系研究，发现了一类以RBC - 2008为先导化合物的新型强效选择性HDAC6抑制剂，其效力为个位数的纳摩尔。这类组蛋白去乙酰化酶抑制剂具有一种新型药效基团，带有一个选择性靶向HDAC6的依布硫骨架。与它对HDAC6的抑制作用一致，RBC - 2008显著提高了PC - 3细胞中α - 微管蛋白的乙酰化水平。此外，用这些化合物处理导致多种肿瘤细胞系以剂量依赖的方式死亡。这些结果表明依布硒仑和依布硫类似物是HDACs的抑制剂，支持这类化合物进一步进行临床前开发以用于潜在的治疗应用。
