Discovery of Pyridopyrimidinones as Potent and Orally Active Dual Inhibitors of PI3K/mTOR

Abstract

The identification and lead optimization of a series of pyridopyrimidinone derivatives are described as a novel class of efficacious dual PI3K/mTOR inhibitors, resulting in the discovery of <b>31</b>. Compound <b>31</b> exhibited high enzyme activity against PI3K and mTOR, potent suppression of Akt and p70s6k phosphorylation in cell assays, and good pharmacokinetic profile. Furthermore, compound <b>31</b> demonstrated in vivo efficacy in a PC-3M tumor xenograft model.