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 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.