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3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands

[Image: see text] Histone–lysine acetylation is a vital chromatin post-translational modification involved in the epigenetic regulation of gene transcription. Bromodomains bind acetylated lysines, acting as readers of the histone-acetylation code. Competitive inhibitors of this interaction have anti...

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Autores principales: Hewings, David S., Wang, Minghua, Philpott, Martin, Fedorov, Oleg, Uttarkar, Sagar, Filippakopoulos, Panagis, Picaud, Sarah, Vuppusetty, Chaitanya, Marsden, Brian, Knapp, Stefan, Conway, Stuart J., Heightman, Tom D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2011
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188285/
https://www.ncbi.nlm.nih.gov/pubmed/21851057
http://dx.doi.org/10.1021/jm200640v
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author Hewings, David S.
Wang, Minghua
Philpott, Martin
Fedorov, Oleg
Uttarkar, Sagar
Filippakopoulos, Panagis
Picaud, Sarah
Vuppusetty, Chaitanya
Marsden, Brian
Knapp, Stefan
Conway, Stuart J.
Heightman, Tom D.
author_facet Hewings, David S.
Wang, Minghua
Philpott, Martin
Fedorov, Oleg
Uttarkar, Sagar
Filippakopoulos, Panagis
Picaud, Sarah
Vuppusetty, Chaitanya
Marsden, Brian
Knapp, Stefan
Conway, Stuart J.
Heightman, Tom D.
author_sort Hewings, David S.
collection PubMed
description [Image: see text] Histone–lysine acetylation is a vital chromatin post-translational modification involved in the epigenetic regulation of gene transcription. Bromodomains bind acetylated lysines, acting as readers of the histone-acetylation code. Competitive inhibitors of this interaction have antiproliferative and anti-inflammatory properties. With 57 distinct bromodomains known, the discovery of subtype-selective inhibitors of the histone–bromodomain interaction is of great importance. We have identified the 3,5-dimethylisoxazole moiety as a novel acetyl-lysine bioisostere, which displaces acetylated histone-mimicking peptides from bromodomains. Using X-ray crystallographic analysis, we have determined the interactions responsible for the activity and selectivity of 4-substituted 3,5-dimethylisoxazoles against a selection of phylogenetically diverse bromodomains. By exploiting these interactions, we have developed compound 4d, which has IC(50) values of <5 μM for the bromodomain-containing proteins BRD2(1) and BRD4(1). These compounds are promising leads for the further development of selective probes for the bromodomain and extra C-terminal domain (BET) family and CREBBP bromodomains.
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spelling pubmed-31882852011-10-06 3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands Hewings, David S. Wang, Minghua Philpott, Martin Fedorov, Oleg Uttarkar, Sagar Filippakopoulos, Panagis Picaud, Sarah Vuppusetty, Chaitanya Marsden, Brian Knapp, Stefan Conway, Stuart J. Heightman, Tom D. J Med Chem [Image: see text] Histone–lysine acetylation is a vital chromatin post-translational modification involved in the epigenetic regulation of gene transcription. Bromodomains bind acetylated lysines, acting as readers of the histone-acetylation code. Competitive inhibitors of this interaction have antiproliferative and anti-inflammatory properties. With 57 distinct bromodomains known, the discovery of subtype-selective inhibitors of the histone–bromodomain interaction is of great importance. We have identified the 3,5-dimethylisoxazole moiety as a novel acetyl-lysine bioisostere, which displaces acetylated histone-mimicking peptides from bromodomains. Using X-ray crystallographic analysis, we have determined the interactions responsible for the activity and selectivity of 4-substituted 3,5-dimethylisoxazoles against a selection of phylogenetically diverse bromodomains. By exploiting these interactions, we have developed compound 4d, which has IC(50) values of <5 μM for the bromodomain-containing proteins BRD2(1) and BRD4(1). These compounds are promising leads for the further development of selective probes for the bromodomain and extra C-terminal domain (BET) family and CREBBP bromodomains. American Chemical Society 2011-08-18 2011-10-13 /pmc/articles/PMC3188285/ /pubmed/21851057 http://dx.doi.org/10.1021/jm200640v Text en Copyright © 2011 American Chemical Society http://pubs.acs.org This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org.
spellingShingle Hewings, David S.
Wang, Minghua
Philpott, Martin
Fedorov, Oleg
Uttarkar, Sagar
Filippakopoulos, Panagis
Picaud, Sarah
Vuppusetty, Chaitanya
Marsden, Brian
Knapp, Stefan
Conway, Stuart J.
Heightman, Tom D.
3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands
title 3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands
title_full 3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands
title_fullStr 3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands
title_full_unstemmed 3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands
title_short 3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands
title_sort 3,5-dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188285/
https://www.ncbi.nlm.nih.gov/pubmed/21851057
http://dx.doi.org/10.1021/jm200640v
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