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.
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Erin M
EM
Bowers
Gai
G
Yan
Chandrani
C
Mukherjee
Andrew
A
Orry
Ling
L
Wang
Marc A
MA
Holbert
Nicholas T
NT
Crump
Catherine A
CA
Hazzalin
Glen
G
Liszczak
Hua
H
Yuan
Cecilia
C
Larocca
S Adrian
SA
Saldanha
Ruben
R
Abagyan
Yan
Y
Sun
David J
DJ
Meyers
Ronen
R
Marmorstein
Louis C
LC
Mahadevan
Rhoda M
RM
Alani
Philip A
PA
Cole
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