Article
Development of Alkylated Hydrazides as Highly Potent and Selective Class I Histone Deacetylase Inhibitors with T cell Modulatory PropertiesClick to copy article linkArticle link copied!
- Ping SunPing SunDepartment of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle/Saale, GermanyMore by Ping Sun
- Jing WangJing WangSchool of Biomedical Sciences, The Chinese University of Hong Kong, 999077 Hong Kong SAR, ChinaMore by Jing Wang
- Khadija S. KhanKhadija S. KhanSchool of Biomedical Sciences, The Chinese University of Hong Kong, 999077 Hong Kong SAR, ChinaSchool of Pharmacy, The Chinese University of Hong Kong, 999077 Hong Kong SAR, ChinaMore by Khadija S. Khan
- Weiqin YangWeiqin YangSchool of Biomedical Sciences, The Chinese University of Hong Kong, 999077 Hong Kong SAR, ChinaMore by Weiqin Yang
- Billy Wai-Lung NgBilly Wai-Lung NgSchool of Pharmacy, The Chinese University of Hong Kong, 999077 Hong Kong SAR, ChinaMore by Billy Wai-Lung Ng
- Nikita IlmentNikita IlmentDepartment of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle/Saale, GermanyMore by Nikita Ilment
- Matthes ZessinMatthes ZessinDepartment of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle/Saale, GermanyMore by Matthes Zessin
- Emre F. BülbülEmre F. BülbülDepartment of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle/Saale, GermanyMore by Emre F. Bülbül
- Dina RobaaDina RobaaDepartment of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle/Saale, GermanyMore by Dina Robaa
- Frank ErdmannFrank ErdmannDepartment of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle/Saale, GermanyMore by Frank Erdmann
- Matthias SchmidtMatthias SchmidtDepartment of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle/Saale, GermanyMore by Matthias Schmidt
- Christophe RomierChristophe RomierDépartement de Biologie Structurale Intégrative, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, CNRS, INSERM, 67404 Illkirch Cedex, FranceMore by Christophe Romier
- Mike SchutkowskiMike SchutkowskiDepartment of Enzymology, Institute of Biotechnology, Martin-Luther University of Halle-Wittenberg, 06120 Halle/Saale, GermanyMore by Mike Schutkowski
- Alfred Sze-Lok Cheng*Alfred Sze-Lok Cheng*Phone: +85239439842. E-mail: [email protected]School of Biomedical Sciences, The Chinese University of Hong Kong, 999077 Hong Kong SAR, ChinaMore by Alfred Sze-Lok Cheng
- Wolfgang Sippl*Wolfgang Sippl*Phone: +493455525040. E-mail: [email protected]Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle/Saale, GermanyMore by Wolfgang Sippl
Abstract
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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.
Copyright © 2022 American Chemical Society
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This article is cited by 17 publications.
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