Virtual Ligand Screening of the p300/CBP Histone Acetyltransferase: Identification of a Selective Small Molecule Inhibitor
By E. Bowers, Gai Yan, Chandrani Mukherjee, A. Orry, Ling Wang, Marc A. Holbert, N. Crump, C. A. Hazzalin, G. Liszczak, H. Yuan and 9 more. Chemistry and Biology, 2010
629 citations recorded by the source corpus.
Summary The histone acetyltransferase (HAT) p300/CBP is a transcriptional coactivator implicated in many gene regulatory pathways and protein acetylation events. While 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 Ki 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 anti-cancer target.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/d3d5a050f09f66068156c575b4b712deee5dcd90
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Citations in the corpus
- Acetylation of tau inhibits its degradation and contributes to tauopathy. (2010, positive): “Characterization of C646, a Selective p300 Inhibitor C646was identified as one of the putative inhibitors of p300by a computational docking screen (Bowers et al., 2010).”
- Docking and scoring with ICM: the benchmarking results and strategies for improvement (2012, background): “of targets in drug discovery, such as enzymes [17–24], receptors [25–30], ion channels [31, 32] and transport proteins [33–35].”