Virtual Ligand Screening of the P300/CBP Histone Acetyltransferase: Identification of a Selective Small Molecule Inhibitor

Overview

Journal Chem Biol

Publisher Elsevier

Specialties Biochemistry
Biology
Chemistry

Date 2010 Jun 11

PMID 20534345

Citations 316

Authors

Erin M Bowers

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

Soon will be listed here.

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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