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Chem Sci DOI:10.1039/C4SC02130D

Kinetically Selective Inhibitors of Histone Deacetylase 2 (HDAC2) as Cognition Enhancers.

Publication TypeJournal Article
Year of Publication2015
AuthorsWagner, FF, Zhang, Y-L, Fass, DM, Joseph, N, Gale, JP, Weïwer, M, McCarren, P, Fisher, SL, Kaya, T, Zhao, W-N, Reis, SA, Hennig, KM, Thomas, M, Lemercier, BC, Lewis, MC, Guan, JS, Moyer, MP, Scolnick, E, Haggarty, SJ, Tsai, L-H, Holson, EB
JournalChem Sci
Volume6
Issue1
Pages804-815
Date Published2015 Jan 01
ISSN2041-6520
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. Novel ortho-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 of ortho-aminoanilides, that exhibit kinetic selectivity (biased residence time) for HDAC2 versus the highly homologous isoform HDAC1, were identified. These kinetically selective HDAC2 inhibitors (BRD6688 and BRD4884) 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.

DOI10.1039/C4SC02130D
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25642316?dopt=Abstract

Alternate JournalChem Sci
PubMed ID25642316
PubMed Central IDPMC4310013
Grant ListR01 DA028301 / DA / NIDA NIH HHS / United States