Development of Alkylated Hydrazides as Highly Potent and Selective Class I Histone Deacetylase Inhibitors with T cell Modulatory Properties.
Fiche publication
Date publication
novembre 2022
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROMIER Christophe
Tous les auteurs :
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
Lien Pubmed
Résumé
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.
Référence
J Med Chem. 2022 11 30;: