Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.

Original publication

DOI

10.1021/jm301588r

Type

Journal article

Journal

J Med Chem

Publication Date

25/04/2013

Volume

56

Pages

3217 - 3227

Keywords

Acetylation, CREB-Binding Protein, Cell Line, Tumor, Crystallography, X-Ray, Histones, Humans, Inhibitory Concentration 50, Isoxazoles, Ligands, Lysine, Nuclear Proteins, Protein Binding, Structure-Activity Relationship, Transcription Factors