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The histone acetyltransferase (HAT) p300/CBP is a transcriptional coactivator implicated in many gene regulatory pathways and protein acetylation events. Although p300 inhibitors have been reported, a potent, selective, and readily available active-site-directed small molecule inhibitor is not yet known. Here we use a structure-based, in silico screening approach to identify a commercially available pyrazolone-containing small molecule p300 HAT inhibitor, C646. C646 is a competitive p300 inhibitor with a K(i) of 400 nM and is selective versus other acetyltransferases. Studies on site-directed p300 HAT mutants and synthetic modifications of C646 confirm the importance of predicted interactions in conferring potency. Inhibition of histone acetylation and cell growth by C646 in cells validate its utility as a pharmacologic probe and suggest that p300/CBP HAT is a worthy anticancer target.

Original publication

DOI

10.1016/j.chembiol.2010.03.006

Type

Journal article

Journal

Chem Biol

Publication Date

28/05/2010

Volume

17

Pages

471 - 482

Keywords

Acetylation, Animals, Antineoplastic Agents, Benzoates, Binding Sites, Binding, Competitive, Catalytic Domain, Cell Line, Tumor, Computer Simulation, Crystallography, X-Ray, Enzyme Inhibitors, Histone Acetyltransferases, Ligands, Mice, Pyrazoles, Pyrazolones, Small Molecule Libraries, Structure-Activity Relationship, p300-CBP Transcription Factors