Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one as a highly potent, selective Mammalian Target of Rapamycin (mTOR) inhibitor for the treatment of cancer

摘要: The mTOR protein is a master regulator of cell growth and proliferation, inhibitors its kinase activity have the potential to become new class anticancer drugs. Starting from quinoline 1, which was identified in biochemical assay, we developed tricyclic benzonaphthyridinone inhibitor 37 (Torin1), inhibited phosphorylation mTORC1 mTORC2 substrates cells at concentrations 2 10 nM, respectively. Moreover, Torin1 exhibits 1000-fold selectivity for over PI3K (EC50 = 1800 nM) 100-fold binding relative 450 other kinases. efficacious dose 20 mg/kg U87MG xenograft model demonstrated good pharmacodynamic inhibition downstream effectors tumor peripheral tissues. These results demonstrate that useful probe mTOR-dependent phenomena benzonaphthridinones represent promising scaffold further development mTOR-specific with clinica...