Selective inhibition of BET bromodomains.

Journal article

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.

Authors: Filippakopoulos, P; Qi, J; Picaud, S; Shen, Y; Smith, W

• Publication status: Published
• Journal: Nature
• Volume: 468
• Issue: 7327
• Pages: 1067-1073
• Publication date: 2010-12-01
• DOI: 10.1038/nature09504
• EISSN: 1476-4687
• ISSN: 0028-0836
• Language: English
• Keywords: Dihydropyridines; Binding Sites; Azirines; Nuclear Proteins; Transcription Factors; Sequence Alignment; Molecular Sequence Data; Mice; Amino Acid Sequence; Protein Structure, Tertiary; Cell Proliferation; Models, Molecular; Animals; Cell Differentiation; Female; Carcinoma, Squamous Cell; Mice, Nude; Humans; Cell Line, Tumor; Stereoisomerism; Skin Neoplasms; Protein Binding; Recombinant Proteins; Chromatin