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

ID: ALA5150060

Journal: J Med Chem

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

Authors: Sun P, Wang J, Khan KS, Yang W, Ng BW, Ilment N, Zessin M, Bülbül EF, Robaa D, Erdmann F, Schmidt M, Romier C, Schutkowski M, Cheng AS, Sippl W.

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 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.

CiteXplore: 36449385

DOI: 10.1021/acs.jmedchem.2c01132

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