• Home
  • Search Results
  • 3,5-dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands.

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

Journal of medicinal chemistry (2011-08-20)
David S Hewings, Minghua Wang, Martin Philpott, Oleg Fedorov, Sagar Uttarkar, Panagis Filippakopoulos, Sarah Picaud, Chaitanya Vuppusetty, Brian Marsden, Stefan Knapp, Stuart J Conway, Tom D Heightman

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.

Product Number
Product Description

1-Methyl-2-pyrrolidinone, anhydrous, 99.5%
1-Methyl-2-pyrrolidinone, ACS reagent, ≥99.0%
1-Methyl-2-pyrrolidinone, ReagentPlus®, 99%
1-Methyl-2-pyrrolidinone, suitable for HPLC, ≥99%
1-Methyl-2-pyrrolidinone, biotech. grade, ≥99.7%
1-Methyl-2-pyrrolidinone, analytical standard