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The benzoxazinone and dihydroquinoxalinone fragments were employed as novel acetyl lysine mimics in the development of CREBBP bromodomain ligands. While the benzoxazinone series showed low affinity for the CREBBP bromodomain, expansion of the dihydroquinoxalinone series resulted in the first potent inhibitors of a bromodomain outside the BET family. Structural and computational studies reveal that an internal hydrogen bond stabilizes the protein-bound conformation of the dihydroquinoxalinone series. The side chain of this series binds in an induced-fit pocket forming a cation-π interaction with R1173 of CREBBP. The most potent compound inhibits binding of CREBBP to chromatin in U2OS cells.

Original publication

DOI

10.1002/anie.201402750

Type

Journal article

Journal

Angewandte Chemie (International ed. in English)

Publication Date

06/2014

Volume

53

Pages

6126 - 6130

Addresses

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK) http://conway.chem.ox.ac.uk/

Keywords

Cations, Ligands, Protein Binding, Models, Molecular, CREB-Binding Protein, Epigenomics