The PI3K-Akt-mechanistic (formerly mammalian) target of the rapamycin (mTOR) signaling pathway is important in a variety of biological activities, including cellular proliferation, survival, metabolism, autophagy, and immunity. Abnormal PI3K-Akt-mTOR signalling activation can promote transformation by creating a cellular environment conducive to it. Deregulation of such a system in terms of genetic mutations and amplification has been related to several human cancers. Consequently, mTOR has been recognized as a key target for the treatment of cancer, especially for treating cancers with elevated mTOR signaling due to genetic or metabolic disorders. In vitro and in vivo, rapamycin which is an immunosuppressant agent actively suppresses the activity of mTOR and reduces cancer cell growth. As a result, various sirolimus-derived compounds have now been established as therapies for cancer, and now these medications are being investigated in clinical studies. In this updated review, we discuss the usage of sirolimus-derived compounds and other drugs in several preclinical or clinical studies as well as explain some of the challenges involved in targeting mTOR for treating various human cancers.
Recent phase II clinical studies with rapamycin for the treatment of multiple sclerosis have revealed promising outcomes . To limit the potential undesired side effects of current mTOR inhibitors, it is important to identify more potent novel targets. ATP competitive inhibitors of mTOR, for example, OSI-027 and its analogues are promising anticancer drugs . Furthermore, recently revealed crystal structures of the mTOR complex would provide new insights for the advancement of more powerful and efficient mTOR inhibitors in future. The clear-cut efficacy of rapamycin and rapalogues in multiple therapeutic settings has propelled interest to discover new types of inhibitors that may be more potent and eventually with fewer side effects than rapamycin and rapalogues that include ATP competitive mTOR inhibitors. The current review summarizes the use of sirolimus and its derivatives and addresses potential limitations in targeting mTOR signaling for the treatment of cancer.
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