Kinetically selective inhibitors of histone deacetylase 2 (HDAC2) as cognition enhancers
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 p...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
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Royal Society of Chemistry (RSC)
2017
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| Online Access: | http://hdl.handle.net/1721.1/112747 https://orcid.org/0000-0003-1262-0592 |
| _version_ | 1826188512688340992 |
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| author | Wagner, F. F. Zhang, Y.-L. Fass, D. M. Gale, J. P. Weïwer, M. McCarren, P. Fisher, S. L. Kaya, T. Zhao, W.-N. Reis, S. A. Hennig, K. M. Thomas, M. Lemercier, B. C. Lewis, M. C. Moyer, M. P. Scolnick, E. Haggarty, S. J. Holson, E. B. Joseph, Nadine Guan, Jisong Tsai, Li-Huei |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Wagner, F. F. Zhang, Y.-L. Fass, D. M. Gale, J. P. Weïwer, M. McCarren, P. Fisher, S. L. Kaya, T. Zhao, W.-N. Reis, S. A. Hennig, K. M. Thomas, M. Lemercier, B. C. Lewis, M. C. Moyer, M. P. Scolnick, E. Haggarty, S. J. Holson, E. B. Joseph, Nadine Guan, Jisong Tsai, Li-Huei |
| author_sort | Wagner, F. F. |
| collection | MIT |
| description | 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 CKp25 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. |
| first_indexed | 2024-09-23T08:00:48Z |
| format | Article |
| id | mit-1721.1/112747 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T08:00:48Z |
| publishDate | 2017 |
| publisher | Royal Society of Chemistry (RSC) |
| record_format | dspace |
| spelling | mit-1721.1/1127472022-09-23T10:17:49Z Kinetically selective inhibitors of histone deacetylase 2 (HDAC2) as cognition enhancers Wagner, F. F. Zhang, Y.-L. Fass, D. M. Gale, J. P. Weïwer, M. McCarren, P. Fisher, S. L. Kaya, T. Zhao, W.-N. Reis, S. A. Hennig, K. M. Thomas, M. Lemercier, B. C. Lewis, M. C. Moyer, M. P. Scolnick, E. Haggarty, S. J. Holson, E. B. Joseph, Nadine Guan, Jisong Tsai, Li-Huei Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Picower Institute for Learning and Memory Joseph, Nadine Guan, Jisong Tsai, Li-Huei 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 CKp25 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. JPB Foundation Stanley Medical Research Institute 2017-12-14T14:38:26Z 2017-12-14T14:38:26Z 2014-10 2014-07 2017-12-11T19:43:17Z Article http://purl.org/eprint/type/JournalArticle 2041-6520 2041-6539 http://hdl.handle.net/1721.1/112747 Wagner, F. F., et al. “Kinetically Selective Inhibitors of Histone Deacetylase 2 (HDAC2) as Cognition Enhancers.” Chemical Science, vol. 6, no. 1, 2015, pp. 804–15. © The Royal Society of Chemistry https://orcid.org/0000-0003-1262-0592 http://dx.doi.org/10.1039/C4SC02130D Chemical Science Creative Commons Attribution-NonCommercial 3.0 Unported https://creativecommons.org/licenses/by-nc/3.0/ application/pdf Royal Society of Chemistry (RSC) Royal Society of Chemistry |
| spellingShingle | Wagner, F. F. Zhang, Y.-L. Fass, D. M. Gale, J. P. Weïwer, M. McCarren, P. Fisher, S. L. Kaya, T. Zhao, W.-N. Reis, S. A. Hennig, K. M. Thomas, M. Lemercier, B. C. Lewis, M. C. Moyer, M. P. Scolnick, E. Haggarty, S. J. Holson, E. B. Joseph, Nadine Guan, Jisong Tsai, Li-Huei Kinetically selective inhibitors of histone deacetylase 2 (HDAC2) as cognition enhancers |
| title | Kinetically selective inhibitors of histone deacetylase 2 (HDAC2) as cognition enhancers |
| title_full | Kinetically selective inhibitors of histone deacetylase 2 (HDAC2) as cognition enhancers |
| title_fullStr | Kinetically selective inhibitors of histone deacetylase 2 (HDAC2) as cognition enhancers |
| title_full_unstemmed | Kinetically selective inhibitors of histone deacetylase 2 (HDAC2) as cognition enhancers |
| title_short | Kinetically selective inhibitors of histone deacetylase 2 (HDAC2) as cognition enhancers |
| title_sort | kinetically selective inhibitors of histone deacetylase 2 hdac2 as cognition enhancers |
| url | http://hdl.handle.net/1721.1/112747 https://orcid.org/0000-0003-1262-0592 |
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