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- Title
Selective inhibition of BET bromodomains.
- Authors
Filippakopoulos, Panagis; 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
- 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.
- Publication
Nature, 2010, Vol 468, Issue 7327, p1067
- ISSN
1476-4687
- Publication type
Journal Article
- DOI
10.1038/nature09504