Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor.
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.
Bowers
Erin M
EM
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Yan
Gai
G
Mukherjee
Chandrani
C
Orry
Andrew
A
Wang
Ling
L
Holbert
Marc A
MA
Crump
Nicholas T
NT
Hazzalin
Catherine A
CA
Liszczak
Glen
G
Yuan
Hua
H
Larocca
Cecilia
C
Saldanha
S Adrian
SA
Abagyan
Ruben
R
Sun
Yan
Y
Meyers
David J
DJ
Marmorstein
Ronen
R
Mahadevan
Louis C
LC
Alani
Rhoda M
RM
Cole
Philip A
PA
D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D047069:Pyrazolones / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry; D013329:Structure-Activity Relationship; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D001565:Benzoates; D004791:Enzyme Inhibitors; D008024:Ligands; D011720:Pyrazoles; D047069:Pyrazolones; D054852:Small Molecule Libraries; C038362:pyrazolone; D051548:Histone Acetyltransferases; D050880:p300-CBP Transcription Factors