2. Academic Validation
  3. Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor

Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor

  • Chem Biol. 2010 May 28;17(5):471-82. doi: 10.1016/j.chembiol.2010.03.006.
Erin M Bowers 1,  Gai Yan,  Chandrani Mukherjee,  Andrew Orry,  Ling Wang,  Marc A Holbert,  Nicholas T Crump,  Catherine A Hazzalin,  Glen Liszczak,  Hua Yuan,  Cecilia Larocca,  S Adrian Saldanha,  Ruben Abagyan,  Yan Sun,  David J Meyers,  Ronen Marmorstein,  Louis C Mahadevan,  Rhoda M Alani,  Philip A Cole
Affiliations

Affiliation

  • 1 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
PMID: 20534345 DOI: 10.1016/j.chembiol.2010.03.006
Abstract

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.

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