title: Kinetically Selective Inhibitors of Histone Deacetylase 2 (HDAC2) as Cognition Enhancers.
abstract: Aiming towards the development of novel nootropic therapeutics to address the cognitive impairment common to a range of brain disorders, we set out to develop highly selective small molecule inhibitors of HDAC2, a chromatin modifying histone deacetylase implicated in memory formation and synaptic plasticity. Novelortho-aminoanilide inhibitors were designed and evaluated for their ability to selectively inhibit HDAC2 versus the other Class I HDACs. Kinetic and thermodynamic binding properties were essential elements of our design strategy and two novel classes ofortho-aminoanilides, that exhibit kinetic selectivity (biased residence time) for HDAC2 versus the highly homologous isoform HDAC1, were identified. These kinetically selective HDAC2 inhibitors (BRD6688andBRD4884) increased H4K12 and H3K9 histone acetylation in primary mouse neuronal cell culture assays, in the hippocampus of CK-p25 mice, a model of neurodegenerative disease, and rescued the associated memory deficits of these mice in a cognition behavioural model. These studies demonstrate for the first time that selective pharmacological inhibition of HDAC2 is feasible and that inhibition of the catalytic activity of this enzyme may serve as a therapeutic approach towards enhancing the learning and memory processes that are affected in many neurological and psychiatric disorders.
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA.
authors: F F
authors: FF
authors: Wagner
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA.
authors: Y-L
authors: YL
authors: Zhang
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA ; SL Fisher Consulting, LLC, PO Box 3052, Framingham, Massachusetts, USA.
authors: D M
authors: DM
authors: Fass
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA ; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Howard Hughes Medical Institute, Cambridge, Massachusetts, USA.
authors: N
authors: N
authors: Joseph
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA.
authors: J P
authors: JP
authors: Gale
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA.
authors: M
authors: M
authors: Weïwer
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA.
authors: P
authors: P
authors: McCarren
authors: SL Fisher Consulting, LLC, PO Box 3052, Framingham, Massachusetts, USA.
authors: S L
authors: SL
authors: Fisher
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA.
authors: T
authors: T
authors: Kaya
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA ; Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology and Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.
authors: W-N
authors: WN
authors: Zhao
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA ; Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology and Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.
authors: S A
authors: SA
authors: Reis
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA ; Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology and Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.
authors: K M
authors: KM
authors: Hennig
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA.
authors: M
authors: M
authors: Thomas
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA.
authors: B C
authors: BC
authors: Lemercier
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA.
authors: M C
authors: MC
authors: Lewis
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA ; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Howard Hughes Medical Institute, Cambridge, Massachusetts, USA.
authors: J S
authors: JS
authors: Guan
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA.
authors: M P
authors: MP
authors: Moyer
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA.
authors: E
authors: E
authors: Scolnick
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA ; Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology and Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.
authors: S J
authors: SJ
authors: Haggarty
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA ; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Howard Hughes Medical Institute, Cambridge, Massachusetts, USA.
authors: L-H
authors: LH
authors: Tsai
authors: Stanley Center for Psychiatric Research; Broad Institute of Harvard and MIT; 7 Cambridge Center, Cambridge, Massachusetts, USA.
authors: E B
authors: EB
authors: Holson
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