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J Med Chem. 2018 Nov 21;61(22):10000-10016. doi: 10.1021/acs.jmedchem.8b01087. Epub 2018 Nov 8.

Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants.

Author information

1
Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Département de Biologie Structurale Intégrative , Université de Strasbourg, Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Santé et de la Recherche Médicale (INSERM U1258) , 1 rue Laurent Fries , 67404 Illkirch Cedex , France.
2
Institute of Pharmacy , Martin-Luther-Universität Halle-Wittenberg , Wolfgang-Langenbeck-Straße 4 , 06120 Halle/Saale , Germany.
3
Institute of Pharmaceutical Sciences , Albert-Ludwigs-Universität Freiburg , Albertstraße 25 , 79104 Freiburg , Germany.
4
CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille , Université de Lille , F-59000 Lille , France.
5
Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire (IBMC), UPR 9004 du CNRS , Université de Strasbourg , 15 Rue René Descartes , 67084 Strasbourg Cedex , France.
6
Institute of Pharmaceutical and Medicinal Chemistry , University of Münster , Corrensstraße 48 , 48149 Münster , Germany.
7
Graduate School of Medical Science , Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-Cho, Sakyo-Ku , 606-0823 Kyoto , Japan.
8
CREST , Japan Science and Technology Agency (JST) , 4-1-8 Honcho Kawaguchi , 332-0012 Saitama , Japan.
9
Department of Chemistry, Institute of Organic Chemistry , University of Hamburg , Martin-Luther-King-Platz 6 , 20146 Hamburg , Germany.

Abstract

Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.

PMID:
30347148
DOI:
10.1021/acs.jmedchem.8b01087
[Indexed for MEDLINE]

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