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3,5-dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands.

Authors
  • Hewings, David S1
  • Wang, Minghua
  • Philpott, Martin
  • Fedorov, Oleg
  • Uttarkar, Sagar
  • Filippakopoulos, Panagis
  • Picaud, Sarah
  • Vuppusetty, Chaitanya
  • Marsden, Brian
  • Knapp, Stefan
  • Conway, Stuart J
  • Heightman, Tom D
  • 1 Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Oct 13, 2011
Volume
54
Issue
19
Pages
6761–6770
Identifiers
DOI: 10.1021/jm200640v
PMID: 21851057
Source
Medline
Language
English
License
Unknown

Abstract

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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