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Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor
- Source :
- Chemistry and biology. 17(5)
- Publication Year :
- 2010
-
Abstract
- SummaryThe 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 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 anticancer target.
- Subjects :
- Lysine Acetyltransferases
Clinical Biochemistry
Antineoplastic Agents
P300-CBP Transcription Factors
Crystallography, X-Ray
Ligands
Benzoates
Binding, Competitive
Biochemistry
Small Molecule Libraries
Mice
Structure-Activity Relationship
Catalytic Domain
Cell Line, Tumor
Drug Discovery
Animals
Computer Simulation
p300-CBP Transcription Factors
Enzyme Inhibitors
Pyrazolones
Molecular Biology
Histone Acetyltransferases
Pharmacology
Binding Sites
biology
Acetylation
DNA
General Medicine
Histone acetyltransferase
Small molecule
CHEMBIO
Histone
biology.protein
Pyrazoles
Molecular Medicine
CELLBIO
Subjects
Details
- Language :
- English
- ISSN :
- 18791301 and 10745521
- Volume :
- 17
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Chemistry and biology
- Accession number :
- edsair.doi.dedup.....181058e1c11f874932a27365270ec131