西亞試劑：Selective inhibition of BET bromodomains

Selective inhibition of BET bromodomains
Panagis Filippakopoulos1,10, Jun Qi2,10, Sarah Picaud1,10, Yao Shen3, William B. Smith2, Oleg Fedorov1, Elizabeth M. Morse2, Tracey Keates1, Tyler T. Hickman4, Ildiko Felletar1, Martin Philpott1, Shonagh Munro5, Michael R. McKeown2,6, Yuchuan Wang7, Amanda L. Christie8, Nathan West2, Michael J. Cameron4, Brian Schwartz4, Tom D. Heightman1, Nicholas La Thangue5, Christopher A. French4, Olaf Wiest3, Andrew L. Kung8,9, Stefan Knapp1,5 & James E. Bradner2,6

1Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK
2Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA
3Walther Cancer Research Center and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA
4Department of Pathology, Brigham & Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA
5Department of Clinical Pharmacology, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK
6Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA
7Department of Imaging, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA
8Lurie Family Imaging Center, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA
9Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children’s Hospital, Boston, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA

 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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