Selective inhibition of BET bromodomains.

Panagis Filippakopoulos, Jun Qi, Sarah Picaud, Yao Shen, William B Smith, Oleg Fedorov, Elizabeth M Morse, Tracey Keates, Tyler T Hickman, Ildiko Felletar, Martin Philpott, Shonagh Munro, Michael R McKeown, Yuchuan Wang, Amanda L Christie, Nathan West, Michael J Cameron, Brian Schwartz, Tom D Heightman, Nicholas La Thangue, Christopher A French, Olaf Wiest, Andrew L Kung, Stefan Knapp, James E Bradner

文献索引：Nature 468(7327) , 1067-73, (2010)

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摘要

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.