Development of Alkylated Hydrazides as Highly Potent and Selective Class I Histone Deacetylase Inhibitors with T cell Modulatory Properties

Abstract

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 <i>n</i>-hexyl side chain attached to the hydrazide moiety shows HDAC8 selectivity <i>in vitro</i>. Analysis of the mode of inhibition of the most promising compound <b>7d</b> against HDAC8 revealed a substrate-competitive binding mode. <b>7d</b> 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 <b>7d</b> (10 mg/kg) in C57BL/6 mice increased <i>interleukin-2</i> 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.