Selective inhibition of BET bromodomains

Article

关键词: ABL TYROSINE KINASE;    PROTEIN BRD4;    P-TEFB;    AGGRESSIVE CARCINOMA;    MITOTIC CHROMOSOMES;    SIGNAL-TRANSDUCTION;    STRUCTURAL BASIS;    CHEMICAL PROBES;    IN-VIVO;    LEUKEMIA;   

DOI  :  10.1038/nature09504

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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