@article{94e6480e6eb04c0782671cd9114ca24c,
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.",
author = "Panagis Filippakopoulos and Jun Qi and Sarah Picaud and Yao Shen and Smith, {William B.} and Oleg Fedorov and Morse, {Elizabeth M.} and Tracey Keates and Hickman, {Tyler T.} and Ildiko Felletar and Martin Philpott and Shonagh Munro and McKeown, {Michael R.} and Yuchuan Wang and Christie, {Amanda L.} and Nathan West and Cameron, {Michael J.} and Brian Schwartz and Heightman, {Tom D.} and {La Thangue}, Nicholas and French, {Christopher A.} and Olaf Wiest and Kung, {Andrew L.} and Stefan Knapp and Bradner, {James E.}",
note = "Funding Information: Acknowledgements We are grateful to U. Oppermann, S. M{\"u}ller, S. Sallan, C. Lathan, P. Rahl, R. Young, K. Lee and K. Shaw for discussions and sharing unpublished information; K. Agu, S. Johnston and L. Li for analytical chemistry support; J. Daley for flow cytometry support; T. Bowman, T. Caron, C. Marvin and S. Rodig for immunohistochemistry; and A. Bass for sharing cell lines. The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., Inc., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research and the Wellcome Trust. This research was supported by a Graduate Fellowship from the Chemistry-Biochemistry-Biology Interface Program at the University of Notre Dame, NIGMS T32-075762 (to Y.S.), the DF/HCC (to C.A.F. and J.E.B.), the National Institutes of Health, the Burroughs Wellcome Fund, and the Leukemia & Lymphoma Society (to J.E.B.).",
year = "2010",
month = dec,
day = "23",
doi = "10.1038/nature09504",
language = "English (US)",
volume = "468",
pages = "1067--1073",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7327",
}