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Issue 1, 2015

Kinetically selective inhibitors of histone deacetylase 2 (HDAC2) as cognition enhancers

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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.

Graphical abstract: Kinetically selective inhibitors of histone deacetylase 2 (HDAC2) as cognition enhancers

Supplementary files

Article information


Submitted
17 Jul 2014
Accepted
10 Sep 2014
First published
09 Oct 2014

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2015,6, 804-815
Article type
Edge Article
Author version available

Kinetically selective inhibitors of histone deacetylase 2 (HDAC2) as cognition enhancers

F. F. Wagner, Y.-L. Zhang, D. M. Fass, N. Joseph, J. P. Gale, M. Weïwer, P. McCarren, S. L. Fisher, T. Kaya, W.-N. Zhao, S. A. Reis, K. M. Hennig, M. Thomas, B. C. Lemercier, M. C. Lewis, J. S. Guan, M. P. Moyer, E. Scolnick, S. J. Haggarty, L.-H. Tsai and E. B. Holson, Chem. Sci., 2015, 6, 804 DOI: 10.1039/C4SC02130D

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