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.

Mammalian target of rapamycin signaling is involved in the vasculogenic mimicry of glioma via hypoxia-inducible factor-1α

“…In the past 10 years, several agents have been designed to target the mTOR pathway and many other mTOR signaling pathway inhibitors are being studied in clinical trials. Temsirolimus, everolimus, and ridaforolimus are rapalogs that share the same mechanism of action but differ in pharmacokinetic properties because of different substitutions at position C-40 of rapamycin (27,43). The present study found and explained, for the first time, the mechanisms of mTOR participation in the alternative form of tumor blood supply, VM, which provides a novel potential therapeutic target for gliomas.…”

Multiple Stimuli-Responsive Hydrogels for Metal-Based Drug Therapy

“…Moreover, from an interesting point of view in clinical practice, the interaction of cisplatin with temsirolimus was also reported [26]. The temsirolimus is a rapamycin ester, a machrolid antibiotic used as an immunosuppressor drug in the prevention of transplants rejection [31,32]. This immunosuppressor drug is not cytotoxic by itself, but is able to synergistically increase the cytotoxicity of cisplatin.…”

m-TOR Inhibitors in the Current Practice

“…Probably this is related to the fact that rapalogs are primarily cytostatic, and therefore effective as disease stabilizers rather than for regression, hence the response rate in solid tumors where rapalogs have been used as a single-agent therapy have been modest [49][50][51][52]. Another reason for the limited success is the presence of feedback loop between mTORC1 and AKT in certain tumor cells.…”