Kinetic and structural insights into the binding of histone deacetylase 1 and 2 (HDAC1, 2) inhibitors
| Autor: | Stefan Steinbacher, Michel Weïwer, Surya A. Reis, Peter Müller, Peter Reinemer, Adrian Schomburg, Jennifer P. Gale, Daniel M. Fass, Stephen J. Haggarty, Krista M. Hennig, Edward B. Holson, Yan-Ling Zhang, Méryl Thomas, Florence F. Wagner, Stewart L. Fisher, Arthur J. Campbell, Wen-Ning Zhao, Martin R. Jefson |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Structural similarity Clinical Biochemistry Histone Deacetylase 2 Pharmaceutical Science Histone Deacetylase 1 Biochemistry Histones Mice 03 medical and health sciences 0302 clinical medicine Drug Discovery Animals Humans Anilides Molecular Biology Cells Cultured Amination biology Chemistry Histone deacetylase 2 Organic Chemistry Acetylation Receptor–ligand kinetics HDAC1 Chromatin Histone Deacetylase Inhibitors Molecular Docking Simulation Kinetics 030104 developmental biology Histone 030220 oncology & carcinogenesis biology.protein Molecular Medicine Selectivity |
| Zdroj: | Bioorganic & Medicinal Chemistry. 24:4008-4015 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2016.06.040 |
| Popis: | The structure-activity and structure-kinetic relationships of a series of novel and selective ortho-aminoanilide inhibitors of histone deacetylases (HDACs) 1 and 2 are described. Different kinetic and thermodynamic selectivity profiles were obtained by varying the moiety occupying an 11Å channel leading to the Zn(2+) catalytic pocket of HDACs 1 and 2, two paralogs with a high degree of structural similarity. The design of these novel inhibitors was informed by two ligand-bound crystal structures of truncated hHDAC2. BRD4884 and BRD7232 possess kinetic selectivity for HDAC1 versus HDAC2. We demonstrate that the binding kinetics of HDAC inhibitors can be tuned for individual isoforms in order to modulate target residence time while retaining functional activity and increased histone H4K12 and H3K9 acetylation in primary mouse neuronal cell culture assays. These chromatin modifiers, with tuned binding kinetic profiles, can be used to define the relation between target engagement requirements and the pharmacodynamic response of HDACs in different disease applications. |
| Databáze: | OpenAIRE |
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