Author/Authors :
Erin M. Bowers، نويسنده , , Gai Yan، نويسنده , , Chandrani Mukherjee، نويسنده , , Andrew Orry، نويسنده , , Ling Wang، نويسنده , , Marc A. Holbert، نويسنده , , Nicholas T. Crump، نويسنده , , Catherine A. Hazzalin، نويسنده , , Glen Liszczak، نويسنده , , Hua-Yuan Tseng، نويسنده , , Cecilia Larocca، نويسنده , , S. Adrian Saldanha، نويسنده , , Ruben Abagyan and Jens Schneider-Mergener، نويسنده , , Yan Sun، نويسنده , , David J. Meyers، نويسنده , , Ronen Marmorstein، نويسنده , , Loui، نويسنده ,
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 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.
