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Recent advances in the discovery of small molecule mTOR inhibitors.

Mammalian target of rapamycin (mTOR) belongs to the atypical kinase family of phosphatidylinositol-3-kinase-related kinase and function as a master regulators of the switch between catabolic and anabolic metabolism. In the last decade mTOR has emerged as a therapeutic target for various diseases such as cancer, inflammation and metabolic disorders. mTOR plays a crucial role in the PI3K/AKT/PDK1 pathway. In this review we will provide an overview of both selective and nonselective mTOR inhibitors. Since rapamycin and rapalogs have been reviewed before, more emphasis has been placed on nonrapamycin-based small-molecule inhibitors and their modulation of mTOR selectivity. Recent efforts in obtaining mTOR-selective inhibitors have produced a range of compounds with more than 1000-fold selectivity over PI3K, but it is still a matter of debate whether an mTOR-selective inhibitor will be of more clinical significance over a PI3K/AKT/mTOR inhibitor.