jq1-compound and Skin-Neoplasms

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.

Topics: Amino Acid Sequence; Animals; Azirines; Binding Sites; Carcinoma, Squamous Cell; Cell Cycle Proteins; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Chromatin; Dihydropyridines; Female; Humans; Mice; Mice, Nude; Models, Molecular; Molecular Sequence Data; Nuclear Proteins; Protein Binding; Protein Structure, Tertiary; Recombinant Proteins; Sequence Alignment; Skin Neoplasms; Stereoisomerism; Transcription Factors