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

  • J Med Chem. 2022 Dec 22;65(24):16313-16337. doi: 10.1021/acs.jmedchem.2c01132.
Ping Sun  1 ,  Jing Wang  2 ,  Khadija S Khan  2  3 ,  Weiqin Yang  2 ,  Billy Wai-Lung Ng  3 ,  Nikita Ilment  1 ,  Matthes Zessin  1 ,  Emre F Bülbül  1 ,  Dina Robaa  1 ,  Frank Erdmann  1 ,  Matthias Schmidt  1 ,  Christophe Romier  4 ,  Mike Schutkowski  5 ,  Alfred Sze-Lok Cheng  2 ,  Wolfgang Sippl  1
Affiliations
  • 1. Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle/Saale, Germany.
  • 2. School of Biomedical Sciences, The Chinese University of Hong Kong, 999077 Hong Kong SAR, China.
  • 3. School of Pharmacy, The Chinese University of Hong Kong, 999077 Hong Kong SAR, China.
  • 4. Département de Biologie Structurale Intégrative, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, CNRS, INSERM, 67404 Illkirch Cedex, France.
  • 5. Department of Enzymology, Institute of Biotechnology, Martin-Luther University of Halle-Wittenberg, 06120 Halle/Saale, Germany.
PMID: 36449385 DOI: 10.1021/acs.jmedchem.2c01132
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.