Selective inhibition of BET bromodomains

Panagis Filippakopoulos, Jun Qi, Sarah Picaud, Yao Shen, William B. Smith, Oleg Fedorov, Elizabeth M. Morse, Tracey Keates, Tyler T. Hickman, Ildiko Felletar, Martin Philpott, Shonagh Munro, Michael R. McKeown, Yuchuan Wang, Amanda L. Christie, Nathan West, Michael J. Cameron, Brian Schwartz, Tom D. Heightman, Nicholas La ThangueChristopher A. French, Olaf Wiest, Andrew L. Kung, Stefan Knapp, James E. Bradner

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1067-1073
Number of pages7
JournalNature
Volume468
Issue number7327
DOIs
StatePublished - Dec 23 2010

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    Filippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W. B., Fedorov, O., Morse, E. M., Keates, T., Hickman, T. T., Felletar, I., Philpott, M., Munro, S., McKeown, M. R., Wang, Y., Christie, A. L., West, N., Cameron, M. J., Schwartz, B., Heightman, T. D., ... Bradner, J. E. (2010). Selective inhibition of BET bromodomains. Nature, 468(7327), 1067-1073. https://doi.org/10.1038/nature09504