Mechanisms of Rapamycin Inhibition on mTOR and Drug Design



The phosphoinositide 3-kinase related kinases (PIKKs) are a family of serine/threonine protein kinases that play important roles in multiple significant signaling pathways and some of them have close relationships with a variety of human diseases. Several structures of PIKKs determined by cryo-electron microscopy and X-ray crystallography have been published recently. Among these structures, mTOR-related complexes, especially mTOR complex 1 (mTORC1) is best studied. mTOR-related structures suggest that the binding of rapamycin to mTOR can generate steric hindrance to narrow the access to the recessed active site and thus block the recruitment of substrates, which induces the inhibition of mTOR activity. mTOR signaling is often hyper-active in multiple cancer types and inhibition of mTOR is an available strategy in tackling cancers. Rapamycin is the natural inhibitor of mTOR, but it has not been taken into cancer therapy because of its poor pharmacokinetic properties. Therefore, rapamycin analogues (called rapalogues) are developed and some rapalogues have been clinically applied to the treatment of diseases including soft tissue and bone sarcoma, breast cancer and renal cancer. Unfortunately, these rapalogues have some drawbacks both in research and cancer therapy. Hence, novel types of inhibitors are being explored, such as ATP-competitive inhibitors. There is still a long way to the development of mTOR-targeted drugs that have significant effects on diseases, and combination of several therapeutic methods will help to improve cancer therapy. Design of novel and selective inhibitor drugs based on mTOR-related structures awaits more structural and functional information of mTORC1 and mTORC2.


mTOR, Structure, Diseases, mTOR-targeted drug design, Rapalogue.


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