Histone deacetylases (HDACs) are epigenetic regulators and additionally control the activity of non-histone substrates. We recently demonstrated that inhibition of HDAC8 overexpressed in various of cancers reduces hepatocellular carcinoma tumorigenicity in a T cell-dependent manner. Here, we present alkylated hydrazide-based class I HDAC inhibitors in which the n-hexyl side chain attached to the hydrazide moiety shows HDAC8 selectivity in vitro. Analysis of the mode of inhibition of the most promising compound 7d against HDAC8 revealed a substrate-competitive binding mode. 7d marked induced acetylation of the HDAC8 substrates H3K27 and SMC3 but not tubulin in CD4⁺ T lymphocytes, and significantly upregulated gene expressions for memory and effector functions. Furthermore, intraperitoneal injection of 7d (10 mg/kg) in C57BL/6 mice increased interleukin-2 expression in CD4⁺ T cells and CD8⁺ T cell proportion with no apparent toxicity. This study expands a novel chemotype of HDAC8 inhibitors with T cell modulatory properties for future therapeutic applications.

中文翻译：

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烷基化酰肼作为具有 T 细胞调节特性的高效和选择性 I 类组蛋白脱乙酰酶抑制剂的开发

组蛋白脱乙酰酶 (HDAC) 是表观遗传调节剂，另外还控制非组蛋白底物的活性。我们最近证明，抑制在各种癌症中过表达的 HDAC8 会以 T 细胞依赖性方式降低肝细胞癌的致瘤性。在这里，我们提出了基于烷基化酰肼的 I 类 HDAC 抑制剂，其中连接到酰肼部分的正己基侧链在体外表现出 HDAC8 选择性。对最有希望的化合物7d对 HDAC8的抑制模式的分析揭示了一种底物竞争性结合模式。7d显着诱导 HDAC8 底物 H3K27 和 SMC3 的乙酰化，但不诱导 CD4 ^{+中的微管蛋白}T 淋巴细胞，并显着上调记忆和效应功能的基因表达。此外，在 C57BL/6 小鼠中腹腔注射7d（10 mg/kg）可增加CD4 ⁺ T 细胞和 CD8 ^{+ T 细胞比例中的}白细胞介素 2表达，且无明显毒性。本研究扩展了具有 T 细胞调节特性的 HDAC8 抑制剂的新型化学型，用于未来的治疗应用。