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

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 -hexyl side chain attached to the hydrazide moiety shows HDAC8 selectivity . Analysis of the mode of inhibition of the most promising compound against HDAC8 revealed a substrate-competitive binding mode. 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 (10 mg/kg) in C57BL/6 mice increased 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.