1333896-49-3Relevant articles and documents
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.
, p. 6761 - 6770 (2011/12/04)
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 IC50 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.
