title: Selective inhibition of BET bromodomains.
abstract: Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.
authors.affiliation: Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.forename: Sarah
authors.initials: S
authors.lastname: Picaud
authors.forename: Yao
authors.initials: Y
authors.lastname: Shen
authors.forename: William B
authors.initials: WB
authors.lastname: Smith
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Morse
authors.forename: Tracey
authors.initials: T
authors.lastname: Keates
authors.forename: Tyler T
authors.initials: TT
authors.lastname: Hickman
authors.forename: Ildiko
authors.initials: I
authors.lastname: Felletar
authors.forename: Martin
authors.initials: M
authors.lastname: Philpott
authors.forename: Shonagh
authors.initials: S
authors.lastname: Munro
authors.forename: Michael R
authors.initials: MR
authors.lastname: McKeown
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Christie
authors.forename: Nathan
authors.initials: N
authors.lastname: West
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cameron
authors.forename: Brian
authors.initials: B
authors.lastname: Schwartz
authors.forename: Tom D
authors.initials: TD
authors.lastname: Heightman
authors.forename: Nicholas
authors.initials: N
authors.lastname: La Thangue
authors.forename: Christopher A
authors.initials: CA
authors.lastname: French
authors.forename: Olaf
authors.initials: O
authors.lastname: Wiest
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001389:Azirines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002294:Carcinoma, Squamous Cell / Q000503:physiopathology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D012878:Skin Neoplasms / Q000503:physiopathology; D013237:Stereoisomerism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D001389:Azirines; D018797:Cell Cycle Proteins; D002843:Chromatin; D004095:Dihydropyridines; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C069267:diazipine