Unknown

Dataset Information

0

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


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 ?M 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.

SUBMITTER: Hewings DS 

PROVIDER: S-EPMC3188285 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

altmetric image

Publications


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  ...[more]

Similar Datasets

| S-EPMC3640414 | biostudies-literature
| S-EPMC3441041 | biostudies-literature
| S-EPMC4032195 | biostudies-literature
| S-ECPF-GEOD-30700 | biostudies-other
| S-EPMC5089653 | biostudies-literature
2013-07-14 | E-GEOD-30700 | biostudies-arrayexpress
2013-07-14 | GSE30700 | GEO
| S-EPMC8491147 | biostudies-literature
| S-EPMC4695401 | biostudies-literature
| S-EPMC4996381 | biostudies-literature