title: Kinetic and structural insights into the binding of histone deacetylase 1 and 2 (HDAC1, 2) inhibitors.
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 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.
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA, USA. Electronic address: fwagner@broadinstitute.org.
authors.forename: Florence F
authors.initials: FF
authors.lastname: Wagner
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA, USA.
authors.forename: Michel
authors.initials: M
authors.lastname: Weïwer
authors.affiliation: Proteros Biostructures GmbH, Bunsenstr. 7a, 82152 Martinsried, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Steinbacher
authors.affiliation: Proteros Biostructures GmbH, Bunsenstr. 7a, 82152 Martinsried, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Schomburg
authors.affiliation: Proteros Biostructures GmbH, Bunsenstr. 7a, 82152 Martinsried, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Reinemer
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA, USA.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Gale
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA, USA.
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Campbell
authors.affiliation: SL Fisher Consulting, LLC, 18 Harrington Road, Framingham, MA, USA.
authors.forename: Stewart L
authors.initials: SL
authors.lastname: Fisher
authors.affiliation: Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology and Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Wen-Ning
authors.initials: WN
authors.lastname: Zhao
authors.affiliation: Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology and Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Surya A
authors.initials: SA
authors.lastname: Reis
authors.affiliation: Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology and Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Krista M
authors.initials: KM
authors.lastname: Hennig
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA, USA.
authors.forename: Méryl
authors.initials: M
authors.lastname: Thomas
authors.affiliation: X-ray Diffraction Facility, MIT Department of Chemistry, 77 Massachussetts Avenue, 2-325, Cambridge, MA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Müller
authors.affiliation: Rodin Therapeutics Inc., 400 Technology Square, 10th Floor, Cambridge, MA, USA.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Jefson
authors.affiliation: Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology and Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Fass
authors.affiliation: Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology and Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA, USA.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA, USA. Electronic address: EHolson@atlasventure.com.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Holson
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000586:Amination; D000813:Anilides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051379:Mice; D062105:Molecular Docking Simulation
chemical_list: D000813:Anilides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2
keywords: Acetylation; HDAC inhibitors; Isoform selectivity; Kinetic selectivity; Target engagement