Selective inhibition of BET bromodomains.
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.
Filippakopoulos
Panagis
P
Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.
Qi
Jun
J
Picaud
Sarah
S
Shen
Yao
Y
Smith
William B
WB
Fedorov
Oleg
O
Morse
Elizabeth M
EM
Keates
Tracey
T
Hickman
Tyler T
TT
Felletar
Ildiko
I
Philpott
Martin
M
Munro
Shonagh
S
McKeown
Michael R
MR
Wang
Yuchuan
Y
Christie
Amanda L
AL
West
Nathan
N
Cameron
Michael J
MJ
Schwartz
Brian
B
Heightman
Tom D
TD
La Thangue
Nicholas
N
French
Christopher A
CA
Wiest
Olaf
O
Kung
Andrew L
AL
Knapp
Stefan
S
Bradner
James E
JE
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
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