2. Academic Validation
  3. Selective inhibition of BET bromodomains

Selective inhibition of BET bromodomains

  • Nature. 2010 Dec 23;468(7327):1067-73. doi: 10.1038/nature09504.
Panagis Filippakopoulos 1,  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 Thangue,  Christopher A French,  Olaf Wiest,  Andrew L Kung,  Stefan Knapp,  James E Bradner
Affiliations

Affiliation

  • 1 Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.
PMID: 20871596 DOI: 10.1038/nature09504
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.

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