Discovery of new aminopyrimidine-based phosphoinositide 3-kinase beta (PI3K beta) inhibitors with selectivity over PI3K alpha

Abstract

Phosphatidylinositol-3-kinase beta (PI3K beta) is an important therapeutic target in arterial thrombosis and special types of cancer. In this study, a new series of aminopyridine-based PI3K beta selective inhibitors have been developed by the structure-based design strategy. When incorporated with the phenyl ring on sulfonamide moiety, aminopyrimidine analogs showed good potency on PI3K beta and selectivity over PI3K alpha. Intriguingly, replacement of phenyl group on sulfonamide with naphthyl group enhanced selectivity over PI3K alpha while retaining submicromolar PI3K beta potency. Molecular modeling suggests that increased PI3K beta specificity is caused by the interaction with salt bridge (Lys782-Asp923) and Asp862 that creat a unique pocket in PI3K beta. These results clearly provide useful insight in the design of new PI3K beta inhibitors with high potency and selectivity. (C) 2011 Elsevier Ltd. All rights reserved.