Panagis Filippakopoulos 1 , Jun Qi 2 , Sarah Picaud 1 , Yao Shen 3 , William B. Smith 2 , Oleg Fedorov 1 , Elizabeth M. Morse 2 , Tracey Keates 1 , Tyler T. Hickman 4 , Ildiko Felletar 1 , Martin Philpott 1 , Shonagh Munro 5 , Michael R. McKeown 2 , 9 , Yuchuan Wang 6 , Amanda L. Christie 7 , Nathan West 2 , Michael J. Cameron 4 , Brian Schwartz 4 , Tom D. Heightman 1 , Nicholas La Thangue 5 , Christopher A. French 4 , Olaf Wiest 3 , Andrew L. Kung 7 , 8 , Stefan Knapp 1 , 5 , James E. Bradner 2 , 9
24 September 2010
Epigenetic proteins are intently pursued targets in ligand discovery. To date, 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) which binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity toward a subset of human bromodomains is explained by co-crystal structures with 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 anti-proliferative 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.