Discovery of 2-(2-aminopyrimidin-5-yl)-4-morpholino-N-(pyridin-3-yl)quinazolin-7-amines as novel PI3K/mTOR inhibitors and anticancer agents

In this study, a series of novel 7 or 8-substituted 4-morpholine-quinazoline derivatives was designed and synthesized. Their PI3K alpha inhibitory activities, antiproliferative activities against seven cancer cell lines, namely, PC-3, DU145, MCF-7, BT474, SK-BR-3, U937 and A431, were evaluated in vitro. Compound 17f proved to be a potential drug candidate with high PI3K alpha inhibition activity (IC50 = 4.2 nM) and good antiproliferative activity. Compound 17f was also tested for its inhibitory activities against other kinases, such as PI3K beta, PI3K gamma, PI3K delta and mTOR, its effects on p-Akt (S473) and cell cycle. These results suggested that compound 17f could significantly inhibit the PI3K/Akt/mTOR pathway as a potent PI3K inhibitor and anticancer agent. (C) 2015 Elsevier Masson SAS. All rights reserved.