Updates of mTOR inhibitors

Abstract

Mammalian target of rapamycin (mTOR) is a central controller of cell growth, proliferation, metabolism and angiogenesis. mTOR signaling is often dysregulated in various human diseases and thus attracts great interest in developing drugs that target mTOR. Currently it is known that mTOR functions as two complexes, mTOR complex 1/2 (mTORC1/2). Rapamycin and its analogs (all termed rapalogs) first form a complex with the intracellular receptor FK506 binding protein 12 (FKBP12) and then bind a domain separated from the catalytic site of mTOR, blocking mTOR function. Rapalogs are selective for 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 and resveratrol, have been found to inhibit mTOR as well. Here, we summarize the current findings regarding mTOR signaling pathway and review the updated data about mTOR inhibitors as anticancer agents.

Fig. (1)

IGF-I-mediated mTOR signaling network. mTORC1 consists of mTOR, Raptor, mLST8, PRAS40 and DEPTOR. TSC1/2-Rheb is the major upstream regulator of mTORC1. S6K1 and 4E-BP1 are two best-characterized downstream effector molecules of mTORC1. Activated S6K1 phosphorylates IRS1 and promotes its degradation, and thus attenuates PI3K/Akt signaling. The mTORC2 subunits include mTOR, Rictor, mSin1, mLST8, PROTOR and DEPTOR. The upstream regulation of mTORC2 remains unknown. Arrows represent activation, whereas bars represent inhibition. IRS, insulin receptor substrates; PIP₂, phosphatidylinositol (4, 5)-bisphosphate; PIP₃, phosphatidylinositol-3, 4, 5-trisphosphate; PDK1, phosphoinositide-dependent kinase 1; TSC, tuberous sclerosis complex; Rheb, Ras homolog enriched in brain; AMPK, AMP-activated kinase.

Fig. (2)

Chemical structures of rapalogs, mTOR and PI3K dual-specificity inhibitors, and mTORC1/2 inhibitors. Temsirolimus, everolimus and deforolimus have the indicated O-substitutions at the C-40 hydroxyl (marked with *) of rapamycin.