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[摘要]：The mTOR It protein is a master regulator of cell growth and proliferation, and inhibitors of its kinase activity have the potential to become new class of anticancer drugs. Starting from quinoline I, which was identified in a biochemical mTOR assay, we developed a tricyclic benzonaphthyridinone inhibitor 37 (Torin 1), which inhibited phosphorylation of mTORC1 and mTORC2 substrates in cells at concentrations of 2 and 10 nM, respectively. Moreover, Torin I exhibits 1000-fold selectivity for mTOR over P13K (EC50 = 1800 nM) and exhibits 100-fold binding selectivity relative to 450 other protein kinases. Torin was efficacious at a dose of 20 mg/kg in a U87MG xenograft model and demonstrated good pharmacodynamic inhibition of downstream effectors of mTOR in tumor and per tissues. These results demonstrate that Torin I is a useful probe of mTOR-dependent phenomena and that benzo-naphthridinones represent a promising scaffold for the further development of mTOR-specific inhibitors with the potential for clinical utility. |
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