Target of Rapamycin

Sirolimus (SRL), also termed rapamycin is a macrolide lactone isolated from the ascomycete species Stre-ptomyces hygroscopicus. After binding to its cytosolic receptor FKBP-12 the resulting complex inhibits the multifunctional serine-threonine kinase mTOR (mammalian target of rapamycin). Inhibition of mTOR prevents activation of the p70S6 kinase and successive... 

Rapamycin is an immunosuppressive diug and an inhibitor of S6K1 (also known as p70S6-kinase) which phosphorylates ribosomal S6 protein. S6K1 is activated in response to insulin via activation of Akt. Rapamycin binds to a specific target protein (mTOR, mammalian target of rapamycin) which is functionally located downstream of Akt, but upstream... 

Target of Rapamycin Encoded by TORI and T0R2 in Yeast... 

Target of Rapamycin encoded by TORI and TOR2 in yeast mTOR, replaces FRAP, RAFT, RAPT or SEP in mammals... 

Very large Serine/Threonine kinases and the molecular Target of Rapamycin, a naturally occurring secondary metabolite, TOR proteins function within multiprotein complexes to couple cell growth and stress responses to environmental and developmental cues. 

Insulin and other growth factors result in the phosphorylation of BP-1 at five unique sites. Phosphorylation of BP-1 results in its dissociation from 4E, and it cannot rebind until critical sites are dephosphorylated. The protein kinase responsible has not been identified, but it appears to be different from the one that phos-phorylates 4E. A kinase in the mammalian target of rapamycin (mTOR) pathway, perhaps mTOR itself, is involved. These effects on the activation of 4E explain in part how insuhn causes a marked posttranscriptional... 

Sirolimus, a target of rapamycin inhibitor, works by decreasing the ability of T cells to respond to IL-2. The major adverse events associated with sirolimus are decreased wound healing, hyperlipidemia, and myelosuppression. This agent appears to have promising effects because it may allow calcineurin inhibitor withdrawal in some patients. 

Figure 7.1 Major signaling pathways relevant to this chapter. Simplified schematic diagram of the major signaling pathways which impinge on mRNA translation I. The phosphatidylinositide 3-kinase (PI 3-kinase) pathway II/III. MAP kinases, especially the classical MAP kinase (ERK) pathway and the p38 MAP kinase pathway IV. The mammalian target of rapamycin (mTOR) pathway. Strictly, this diagram shows the rapamycin-sensitive events linked to mTORCl. Selected inhibitors and their sites of action are shown. A numberof components and cross-connections have been omitted for clarity.

Brunn, G.J., Williams, J., Sabers, C., Weiderrecht, G., Lawrence, J. C., and Abraham, R. T. (1996). Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBOJ. 15, 5256-5267. 

Manning, B. D., and Cantley, L. C. (2003). United at last The tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signaling. Biochem. Soc. Trans. 31, 573-578. 

The discovery and characterization of novel small molecule inhibitors that target the ribosome recruitment step of translation initiation is extremely important in order to validate translation initiation as a chemotherapeutic target. Rapamycin, an inhibitor of TOR (target of rapamycin) complex I... 

Everolimus (40 Afinitor Novartis, 2009), a rapamycin analog, is the 42-0-(2-hydroxyethyl) derivative of sirolimus (34), and is marketed as an immunosuppressant by Novartis under the tradename Afinitor for use in advanced renal cell carcinoma.In March 2009, the FDA approved everolimus (40) for use against advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. The drug works similarly to sirolimus as an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, downstream of the PI3K/AKT pathway. Everolimus (40) binds to an intracellular protein, EKBP-12, resulting in an inhibitory... 

Del Bufalo D, Ciuffreda L, TriscinogUo D, Desideri M, Cognetti F, Zupi G Milella M. (2006) Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirohmus. Cancer Res 66 5549-5554. 

Mita MM, Mita AC, Chu QS, Rowinsky EK, Eetterly GJ, Goldston M, Patnaik A, Mathews L, Ricart AD, Mays T, Knowles H, Rivera VM, Kreisberg J, Bedrosian CL, Tolcher AW. (2008) Phase Itrial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573 MK-8669)... 

Chan S. Targeting the mammalian target of rapamycin (mTOR) a new approach to treating cancer. Br J Cancer 2004 91(8) 1420-4. 

Webster AC, Lee VW, Chapman JR, Craig JC. Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients a systematic review and meta-analysis of randomized trials. Transplantation 2006 81(9) 1234-48. 

Another approach to the management of IM resistance is to combine agents that are individually active against CML but have differing mechanisms of action that may allow either additive or synergistic effects in a non-cross-resistant marmer. This approach has been extensively studied in the literature and will not be reviewed in detail here. An excellent discussion of combination therapy is foimd in the reviews by Hochhaus and La Rosee (52,85). Some combination approaches have utilized famesyl transferase inhibition such as lonafamib in combination with IM, inhibitors of the mammalian target of rapamycin (mTOR) in combination with IM and combining mycophenolic acid, an inhibitor of the JAK-STAT pathway. 

A new class of immunosuppressive agents called proliferation-signal inhibitors (PSIs) includes sirolimus (rapamycin) and its derivative everolimus. The mechanism of action of PSIs differs from that of the calcineurin inhibitors. PSIs bind the circulating immunophilin FK506-binding protein 12, resulting in an active complex that blocks the molecular target of rapamycin (mTOR). 

Kunz, J. Henriquez, R. Schneider, U. Deuter-Reinhard, M. Mowa, N.R. Hall, M.N. Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for Gl progression. Cell, 73, 585-596 (1993)... 

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