Rapamycin and mTOR kinase inhibitors

Abstract

Mammalian target of rapamycin (mTOR) is a protein kinase that controls cell growth, proliferation, and survival. mTOR signaling is often upregulated in cancer and there is great interest in developing drugs that target this enzyme. Rapamycin and its analogs bind to a domain separate from the catalytic site to block a subset of mTOR functions. These drugs are extremely selective for mTOR and are already in clinical use for treating cancers, but they could potentially activate an mTOR-dependent survival pathway that could lead to treatment failure. By contrast, small molecules that compete with ATP in the catalytic site would inhibit all of the kinase-dependent functions of mTOR without activating the survival pathway. Several non-selective mTOR kinase inhibitors have been described and here we review their chemical and cellular properties. Further development of selective mTOR kinase inhibitors holds the promise of yielding potent anticancer drugs with a novel mechanism of action.

Fig. 1

mTOR signaling. Growth factor activation of PI3K causes increased production of PI 3,4,5-trisphosphate (PI(3,4,5)P₃). Akt is activated upon binding to PI(3,4,5)P₃ and phosphorylation of Thr308 by phosphoinositide-dependent protein kinase 1 (PDK1) and Ser473 by mTORC2. The TSC1/TSC2 complex inhibits mTORC1 by stimulating the GTPase activity of Rheb, converting it to the inactive GDP-bound state. Akt phosphorylation of TSC2 inhibits the TSC1/TSC2 complex and allows Rheb to remain in the active GTP-bound form. Phosphorylation by AMPK activates TSC2 and opposes the Akt signal. In energy-poor conditions, increased AMP levels allow LKB1 to phosphorylate and activate AMPK. Decreased signaling through Vps34 in the presence of low amino acid levels to inhibit mTOR might be independent of TSC1/TSC2 and Rheb. mTOR is inhibited during hypoxia due to activation of TSC1/TSC2 by REDD1. Rheb-GTP binds to and activates mTORC1. mTORC1 phosphorylates the translation repressor 4EBP1 and S6K at Thr389, leading to its activation. Inhibitors that target the mTOR kinase domain block both mTORC1 and mTORC2, whereas rapamycin only inhibits mTORC1. Upregulation of S6K in cells with hyperactive mTORC1 signaling has a feedback inhibitory effect on Akt. Therefore, treatment with rapamycin leading to inhibition of S6K can upregulate Akt and enhance cell survival. In contrast, mTOR kinase inhibitors block both S6K and Akt activation and should not enhance cell survival. It is not clear how TSC1/TSC2 and Rheb regulate the activity of mTORC2 [24]

Fig. 2

Chemical structure of rapamycin, rapalogs and mTOR kinase inhibitors. Rapalogs have the indicated O-substitutions at the C-40 position of rapamycin (underline)