Review
KeynoteTargeting mammalian target of rapamycin (mTOR) for health and diseases
Keynote
Introduction
Rapamycin is a macrolide that is produced by the bacterium Streptomyces hygroscopicus, which was discovered in a soil sample collected ∼1970 from the Easter Island Rapa Nui, from where the name rapamycin is derived (Box 1). Rapamycin was developed initially by Ayerst as an antifungal agent, but was soon abandoned because of the immunosuppressive effect and rapamycin was largely forgotten during the next decade. In the 20 years following its discovery only a dozen or so papers related to rapamycin were published. However, in the early 1990s the field experienced a dramatic turn of fortune, spurred largely by studies on the mechanism of action of rapamycin and by identification of the drug target. The growth of rapamycin-related research also renewed clinical interests and, in addition to rapamycin, several rapamycin analogs have been synthesized and tested in clinical trials. In 1997 rapamycin was approved by the FDA as an anti-rejection drug for kidney transplants.
Entering the 21st century, the field has continued the explosive growth. Recent studies provide significant insights into the molecular architecture of the mammalian target of rapamycin (mTOR) pathway. More importantly, the role of the mTOR pathway as a key process that underlies many human diseases has been either discovered or confirmed. New clinical indications for rapamycin and rapamycin analogs keep arising, and the scope of these is beyond their immunosuppressive activity. Rapamycin and rapamycin analogs are in clinical trials for several conditions such as cancer and cardiovascular diseases. In 2003, the FDA approved the rapamycin-eluting stent, a revolutionary coronary angioplastic procedure. The goal of this article is to comprehensively review the role of mTOR in the pathology of diverse diseases and areas that are related closely to human health. Detailed analyses of the clinical benefits and potential for the existing inhibitors of mTOR, and new therapeutic opportunities are also presented.
Section snippets
Inhibitors of mTOR: rapamycin and rapamycin derivatives
Rapamycin is the founding member of the family of mTOR inhibitors. Rapamycin includes two separated moieties, the TOR-binding and the FKBP12-binding regions. To be active biologically, rapamycin must form a ternary complex with mTOR and FKBP12, which is a cytosolic binding protein collectively called immunophilin. Therefore, rapamycin acts to induce the dimerization of mTOR and FKBP12. The formation of a rapamycin–FKBP12 complex results in a gain-of-function because the complex binds directly
mTOR and the mTOR signaling network
mTOR is a well-conserved 289 kDa phosphatidylinositol 3-kinase (PI 3-kinase)-related kinase (PIKK) that occurs in all eukaryotic organisms sequenced so far. The structural organization of mTOR is shown in Figure 2a. The C-terminal PIKK domain is conserved most highly and exhibits serine and threonine kinase activity but no lipid kinase activity as seen with other members of the PIKK family [9]. An intact PIKK domain is required for all known functions of TOR 10, 11. The FKBP12-rapamycin-binding
mTOR in health and disease
In the past 5 years, growth has been recognized as a central process in most, if not all, aspects of cell biology. An increasing number of human diseases have been linked to the dysregulation of mTOR, including immunological disorders, cancer, metabolic diseases, cardiovascular diseases and neurological disorders. Intriguingly, most of these are due to aberrant hyperactivity of the mTOR pathway, which makes inhibitors of mTOR potentially effective therapeutics for the treatment of these
Discovery of new inhibitors of mTOR
A major challenge is to identify and understand the long-term negative effects of mTOR inhibitors. Although rapamycin and the currently available rapamycin analogs are well tolerated, their side-effects are not documented fully. Nevertheless, because mTOR is involved in many cellular processes and disease pathways, selective inhibitors that target a subset of mTOR-regulated functions are likely to reduce the undesirable side-effects. By contrast, many tumors are not very responsive to rapamycin
Future perspective and conclusions
We have experienced amazing advances in the understanding of mTOR signaling during the past 15 years. This basic research has inspired clinical studies that reveal crucial roles of mTOR in a range of human disorders. Further research on mTOR will generate new understanding of how cells control their functions, with growth as the centerpiece. They will also reveal molecular details of how malfunctions at various steps lead to disease states, through genetic and/or environmental changes.
Acknowledgement
We apologize for being unable to cite all the relevant publications due to space constraint. Research in the authors’ laboratories was supported by grants from the National Institutes of Health (L.F.L. and X.F.S.Z).
Chi Kwan Tsang
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Cited by (0)
Chi Kwan Tsang
Haiyan Qi
Leroy F. Liu
X.F. Steven Zheng
Dr Tsang is a post-doctoral fellow in pharmacology at Robert Wood Johnson Medical School (RWJMS). He obtained his PhD from Kagoshima University in 2002. Dr Qi is an assistant professor of pharmacology. She received her PhD from New York Medical College in 1996 and post-doctoral training at Princeton University. Dr Liu is a professor and Chairman of Pharmacology at RWJMS. His research area is in cancer therapeutics. Dr Liu is an associate editor for several leading cancer journals, including Cancer Research. He has received many awards and honors, including the Bruce F. Cain Memorial Award for Outstanding Preclinical Research by AACR in 1997. Dr Zheng is University Professor of Pharmacology at RWJMS. He is a pioneer and expert in target of rapamycin (TOR) signaling and mechanism of rapamycin action. He currently serves on the editorial boards of Drug Discovery Today and Translational OncoGenomics. Drs Liu and Zheng are both supported by multiple NIH R01 grants.