title: 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 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.
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: David S
authors.initials: DS
authors.lastname: Hewings
authors.forename: Minghua
authors.initials: M
authors.lastname: Wang
authors.forename: Martin
authors.initials: M
authors.lastname: Philpott
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.forename: Sagar
authors.initials: S
authors.lastname: Uttarkar
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Sarah
authors.initials: S
authors.lastname: Picaud
authors.forename: Chaitanya
authors.initials: C
authors.lastname: Vuppusetty
authors.forename: Brian
authors.initials: B
authors.lastname: Marsden
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Conway
authors.forename: Tom D
authors.initials: TD
authors.lastname: Heightman
mesh_terms: D050882:CREB-Binding Protein / Q000378:metabolism; D018797:Cell Cycle Proteins; D018360:Crystallography, X-Ray; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008239:Lysine / Q000378:metabolism*; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000378:metabolism; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins; D003603:Cytotoxins; D006657:Histones; D007555:Isoxazoles; D008024:Ligands; D008239:Lysine; D009687:Nuclear Proteins; D010626:Phenylethyl Alcohol; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C441289:BRD4 protein, human; C494363:CREBBP protein, human