Selective inhibition of BET bromodomains.
Filippakopoulos, Panagis 1,10; Qi, Jun 2,10; Picaud, Sarah 1,10; Shen, Yao 3; Smith, William B. 2; Fedorov, Oleg 1; Morse, Elizabeth M. 2; Keates, Tracey 1; Hickman, Tyler T. 4; Felletar, Ildiko 1; Philpott, Martin 1; Munro, Shonagh 5; McKeown, Michael R. 2,6; Wang, Yuchuan 7; Christie, Amanda L. 8; West, Nathan 2; Cameron, Michael J. 4; Schwartz, Brian 4; Heightman, Tom D. 1; La Thangue, Nicholas 5; French, Christopher A. 4; Wiest, Olaf 3; Kung, Andrew L. 8,9; Knapp, Stefan 1,5; Bradner, James E. 2,6
[Article] Nature. 468(7327):1067-1073, December 23, 2010.

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: 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.

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