Design, synthesis and pharmacological evaluation of 2-arylurea-1,3,5-triazine derivative (XIN-9): A novel potent dual PI3K/mTOR inhibitor for cancer therapy.

ABSTRACT

Blocking the PI3K/AKT/mTOR pathway has been widely recognized as an attractive cancer therapeutic strategy because of its crucial role in cell growth and survival. In this study, a novel series of 2-arylurea-1,3,5-triazine derivatives had been synthesized and evaluated as highly potent PI3K and mTOR inhibitors. The new compounds exhibited cytotoxic activities against MCF-7, Hela and A549 cancer cell lines (IC50 = 0.03-36.54 µM). The most promising compound XIN-9 exhibited potent inhibition against PI3K and mTOR kinase (IC50 = 23.8 and 10.9 nM). Mechanistic study using real-time PCR revealed the ability of XIN-9 to inhibit PI3K and mTOR. In addition, compound XIN-9 arrested the cell cycle of MCF-7 cells at the G0/G1 phase. XIN-9 also caused a significant dose-dependent increase of early and late apoptotic events. Molecular docking analysis revealed a high binding affinity for XIN-9 toward PI3K and mTOR. Following in vitro studies, XIN-9 was further evaluated in MCF-7 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 41.67% (po, 75 mg/kg). Overall, this work indicated that compound XIN-9 represents a potential anticancer targeting PI3K/AKT/mTOR pathway.