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

• Journal: Nature
• Volume: 468
• Issue: 7327
• Pages: 1067-73
• Publication date: 2010-12-23
• ISSN: 1476-4687
• Language: English
• Subjects: Recombinant Proteins; Stereoisomerism; chemical synthesis; Chromatin; physiopathology; pharmacology; metabolism; Molecular Sequence Data; Skin Neoplasms; Protein Binding; Mice; Amino Acid Sequence; Models, Molecular; Dihydropyridines; Sequence Alignment; Protein Structure, Tertiary; Cell Differentiation; Animals; Binding Sites; Cell Line, Tumor; Cell Proliferation; Carcinoma, Squamous Cell; Mice, Nude; Nuclear Proteins; antagonists and inhibitors; drug effects; Humans; Azirines; Female; Transcription Factors; chemistry