Advances in mTOR inhibitors

Abstract

Mammalian target of rapamycin (mTOR) is the hub of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway, which is one of the most commonly mutated pathways in cancer. mTOR is considered a member of the PI3K-kinase-related kinase (PIKK) superfamily since its C-terminus shares strong homology to the catalytic domain of PI3K. Currently it is known that mTOR functions as two complexes, mTOR complex 1 (mTORC1) and mTORC2. Clinically used rapamycin and rapalogs are allosteric inhibitors of mTORC1 and effective as anticancer agents in various preclinical models. In clinical trials, rapalogs have demonstrated efficacy against certain types of cancer. Recently, a new generation of mTOR inhibitors, which compete with ATP in the catalytic site of mTOR and inhibit both mTORC1 and mTORC2 with a high degree of selectivity, have been developed. Besides, some natural products, such as epigallocatechin gallate (EGCG), caffeine, curcumin, resveratrol and cryptotanshinone, have been found to inhibit mTOR as well. Here, we review the current findings regarding mTOR signaling pathway and discuss the advances in mTOR inhibitors as anticancer agents.