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PMID: 20871596 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Selective inhibition of BET bromodomains.

Nature ·Vol. 468 ·No. 7327 ·2010-12-23 ·Pages 1067-73

Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, Munro S, McKeown MR, Wang Y, Christie AL, West N, Cameron MJ, Schwartz B, Heightman TD, La Thangue N, French CA, Wiest O, Kung AL, Knapp S, Bradner JE

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.

MeSH Terms
Amino Acid Sequence Animals Azirines/chemical synthesis,chemistry,pharmacology Binding Sites Carcinoma, Squamous Cell/physiopathology Cell Cycle Proteins Cell Differentiation/drug effects Cell Line, Tumor Cell Proliferation/drug effects Chromatin/metabolism Dihydropyridines/chemical synthesis,chemistry,pharmacology Female Humans Mice Mice, Nude Models, Molecular Molecular Sequence Data Nuclear Proteins/antagonists & inhibitors,metabolism Protein Binding/drug effects Protein Structure, Tertiary Recombinant Proteins/metabolism Sequence Alignment Skin Neoplasms/physiopathology Stereoisomerism Transcription Factors/antagonists & inhibitors,metabolism
Chemicals
Azirines BRD4 protein, human Cell Cycle Proteins Chromatin Dihydropyridines Nuclear Proteins Recombinant Proteins Transcription Factors diazipine
Authors & Affiliations
25 authors, click to expand affiliations / ORCID
Filippakopoulos Panagis
Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.
Qi Jun
Picaud Sarah
Shen Yao
Smith William B
Fedorov Oleg
Morse Elizabeth M
Keates Tracey
Hickman Tyler T
Felletar Ildiko
Philpott Martin
Munro Shonagh
McKeown Michael R
Wang Yuchuan
Christie Amanda L
West Nathan
Cameron Michael J
Schwartz Brian
Heightman Tom D
La Thangue Nicholas
French Christopher A
Wiest Olaf
Kung Andrew L
Knapp Stefan
Bradner James E
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature09504
Published
2010-12-23
Epub
2010-00-24
Pages
1067-73
Language
English
Region
England
NLM ID
0410462
PMCID
PMC3010259
Subset
IM
Grants
Medical Research Council · G9400953 · United Kingdom
CIHR · Canada
Medical Research Council · G1000807 · United Kingdom
NCI NIH HHS · K08 CA128972 · United States
PHS HHS · T32-075762 · United States
Medical Research Council · G0500905 · United Kingdom
NCI NIH HHS · K08 CA128972-03 · United States
Wellcome Trust · United Kingdom
Cancer Research UK · 13058 · United Kingdom
Databases
PDB
2OSS, 3MXF, 3ONI
Corrections
CommentIn
PMID: 21179160
External Links
PubMed source DOI: 10.1038/nature09504 PMC Full Text View journal details
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