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

Ping Sun , Jing Wang , Khadija S. Khan , Weiqin Yang , Billy Wai-Lung Ng , Nikita Ilment , Matthes Zessin , Emre F. Bülbül , Dina Robaa , Frank Erdmann , Matthias Schmidt , Christophe Romier (1, 2) , Mike Schutkowski , Alfred Sze-Lok Cheng , Wolfgang Sippl

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 IGBMC - Institut de génétique et biologie moléculaire et cellulaire

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.

Domaines: Chimie thérapeutique

Ping Sun, Jing Wang, Khadija S. Khan, Weiqin Yang, Billy Wai-Lung Ng, et al.. Development of Alkylated Hydrazides as Highly Potent and Selective Class I Histone Deacetylase Inhibitors with T cell Modulatory Properties. Journal of Medicinal Chemistry, 2022, 65 (24), pp.16313-16337. ⟨10.1021/acs.jmedchem.2c01132⟩. ⟨hal-04219149⟩