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

A class of 2-arylurea-1,3,5-triazine derivatives (A1-A28) were designed and synthesized. The derivative A9 (XIN-9) with excellent inhibitory activity was screened to be a promising PI3K/mTOR dual inhibitor. [Display omitted] •A novel series 2-arylurea-1, 3, 5-triazine derivatives were designed and characterized.•Select compound XIN-9 as a potential dual inhibitor of PI3K/mTOR.•Compound XIN-9 showed significant cytotoxicity against 8 kinds of cancer cells (MCF-7, Hela, A549, NCI-H1975, PC-9, Ovcar-3, Caco-2 and Hela-MDR), and exhibited variable cytotoxic activities against LO-2 cells.•Potential dual PI3K/mTOR inhibitor XIN-9 arrested the cell cycle of MCF-7 cells at the G0/G1 phase. It also caused a significant dose-dependent increase of early and late apoptotic events.•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). 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.