Kinetic and structural insights into the binding of histone deacetylase 1 and 2 (HDAC1, 2) inhibitors |
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| Institution: | 1. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA, USA;2. Proteros Biostructures GmbH, Bunsenstr. 7a, 82152 Martinsried, Germany;3. SL Fisher Consulting, LLC, 18 Harrington Road, Framingham, MA, USA;4. Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology and Psychiatry, Harvard Medical School, Boston, MA, USA;5. X-ray Diffraction Facility, MIT Department of Chemistry, 77 Massachussetts Avenue, 2-325, Cambridge, MA, USA;6. Rodin Therapeutics Inc., 400 Technology Square, 10th Floor, Cambridge, MA, USA;1. School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210096, PR China;2. College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, PR China;3. Department of Medicinal Chemistry and the Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55414, USA;4. Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA;5. School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China;6. Suzhou Key Laboratory of Biomaterials and Technologies & Collaborative Innovation Center of Suzhou Nano Science and Technology, Suzhou 215123, PR China;1. Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji''nan, Shandong, 250012, PR China;2. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji''nan, Shandong, 250012, PR China;3. Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, SC, 29425, United States;4. Weifang Bochuang International Biological Medicinal Institute, Weifang, Shandong, 261061, PR China;1. School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong Zone, Shanghai, 201203, China;2. Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China;3. Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China;1. Chemical Neurobiology Laboratory, Departments of Neurology & Psychiatry, Massachusetts General Hospital, Center for Genomic Medicine, Harvard Medical School, Boston, MA 02114, USA;2. Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA;3. MGH Frontotemporal Disorders Unit, Gerontology Research Unit, Alzheimer''s Disease Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA;4. Departments of Molecular Genetics, Neuroscience, Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9046, USA;1. Henry Wellcome Laboratories of Structural Biology, Department of Molecular and Cell Biology, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK |
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| Abstract: | 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 11 Å channel leading to the Zn2+ 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. |
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| Keywords: | HDAC inhibitors Isoform selectivity Kinetic selectivity Target engagement Acetylation |
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