title: Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands.
abstract: The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
authors.forename: David S
authors.initials: DS
authors.lastname: Hewings
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Sarah
authors.initials: S
authors.lastname: Martin
authors.forename: Sarah
authors.initials: S
authors.lastname: Picaud
authors.forename: Anthony
authors.initials: A
authors.lastname: Tumber
authors.forename: Christopher
authors.initials: C
authors.lastname: Wells
authors.forename: Monica M
authors.initials: MM
authors.lastname: Olcina
authors.forename: Katherine
authors.initials: K
authors.lastname: Freeman
authors.forename: Andrew
authors.initials: A
authors.lastname: Gill
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Ritchie
authors.forename: David W
authors.initials: DW
authors.lastname: Sheppard
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Russell
authors.forename: Ester M
authors.initials: EM
authors.lastname: Hammond
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Paul E
authors.initials: PE
authors.lastname: Brennan
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Conway
mesh_terms: D000107:Acetylation; D050882:CREB-Binding Protein / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006657:Histones / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008239:Lysine / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000092468:Bromodomain Containing Proteins
chemical_list: D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins; D006657:Histones; D007555:Isoxazoles; D008024:Ligands; D008239:Lysine; D009687:Nuclear Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C494363:CREBBP protein, human