mTOR inhibitors: An overview

Neuhaus, Peter; Klupp, J; Langrehr, Jan M.

doi:10.1053/jlts.2001.24645

Cited by 179 publications

(143 citation statements)

References 102 publications

(146 reference statements)

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“…49 Sirolimus and the 40-O-(2-hydroxyethyl) ester derivation, everolimus, are orally administered, and the efficiency of absorption is modulated by p-glycoproteins (reviewed in ref. 50). Sirolimus has a terminal half-life of 62 hours in stable renal transplant recipients treated with cyclosporine, its steady state is usually reached within 7 to 14 days, and its bioavailability is approximately 15%.…”

Section: Pharmacology Of Sirolimus and Derivativesmentioning

confidence: 99%

“…Sirolimus has a terminal half-life of 62 hours in stable renal transplant recipients treated with cyclosporine, its steady state is usually reached within 7 to 14 days, and its bioavailability is approximately 15%. 50 Both intravenous and oral formulations are under evaluation for temsirolimus and AP23753. In cancer patients, the mean terminal half-life for intravenously administered temsirolimus is 13-22 hours and decreases with increasing dose reflecting alteration in clearance consistent with saturation of distribution sites.…”

Section: Pharmacology Of Sirolimus and Derivativesmentioning

confidence: 99%

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Therapeutic targets: MTOR and related pathways

Dancey¹

2006

Cancer Biology & Therapy

182

134

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The mammalian target of rapamycin (mTOR), a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, has a central role in controlling malignant cellular growth. As a result, mTOR is viewed as an important target for anticancer drug development. Inhibitors of mTOR currently under evaluation in cancer clinical trials are rapamycin (also known as sirolimus, Wyeth) and derivatives temsirolimus (CCI-779, Wyeth), everolimus, (RAD001, Novartis Pharma AG), and AP23573 (Ariad Pharmaceuticals). Preclinical studies suggest that sensitivity to mTOR inhibitors may correlate with activation of the PI3K pathway and/or with aberrant expression of cell cycle regulatory or anti-apoptotic proteins. Clinical trial results show that mTOR inhibitors are well tolerated and may induce prolonged stable disease and tumor regressions in cancer patients. Future research should evaluate optimal, schedule, patient selection, and combination strategies for this novel class of agents.

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Section: Pharmacology Of Sirolimus and Derivativesmentioning

confidence: 99%

Section: Pharmacology Of Sirolimus and Derivativesmentioning

confidence: 99%

Therapeutic targets: MTOR and related pathways

Dancey¹

2006

Cancer Biology & Therapy

182

134

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“…The potential utility of rapamycin and its derivatives as drugs that diminish tissue rejection in transplant patients and cell division in some forms of cancer, particularly those associated with defects in the pTEN tumor suppressor gene, have stimulated interest and research into the mechanisms through which the target of the drug, the Tor protein, regulates cellular processes (1)(2)(3)(4). Moreover, studies in Saccharomyces cerevisiae are contributing significantly to our understanding of the Tor signal transduction pathway in eukaryotic cells.…”

mentioning

confidence: 99%

Methionine Sulfoximine Treatment and Carbon Starvation Elicit Snf1-independent Phosphorylation of the Transcription Activator Gln3 in Saccharomyces cerevisiae

Tate

Rai

Cooper

2005

Journal of Biological Chemistry

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Tor proteins are global regulators situated at the top of a signal transduction pathway conserved from yeast to humans. Specific inhibition of the two Saccharomyces cerevisiae Tor proteins by rapamycin alters many cellular processes and the expression of hundreds of genes. Among the regulated genes are those whose expression is activated by the GATA family transcription activator, Gln3. The extent of Gln3 phosphorylation has been thought to determine its intracellular localization, with phosphorylated and dephosphorylated forms accumulating in the cytoplasm and nucleus, respectively. Data presented here demonstrate that rapamycin and the glutamine synthetase inhibitor, methionine sulfoximine (MSX), although eliciting the same outcomes with respect to Gln3-Myc 13 nuclear accumulation and nitrogen catabolite repression-sensitive transcription, generate diametrically opposite effects on Gln3-Myc 13 phosphorylation. MSX increases Gln3-Myc 13 phosphorylation and rapamycin decreases it. Gln3-Myc 13 phosphorylation levels are regulated by at least three mechanisms as follows: (i) depends on Snf1 kinase as observed during carbon starvation, (ii) is Snf1-independent as observed during both carbon starvation and MSX treatment, and (iii) is rapamycin-induced dephosphorylation. MSX and rapamycin act additively on Gln3-Myc 13 phosphorylation, but MSX clearly predominates. These results suggest that MSX-and rapamycin-inhibited proteins are more likely to function in separate regulatory pathways than they are to function tandemly in a single pathway as thought previously. Furthermore, as we and others have detected thus far, Gln3 phosphorylation/dephosphorylation is not a demonstrably required step in achieving Gln3 nuclear localization and nitrogen catabolite repression-sensitive transcription in response to MSX or rapamycin treatment.

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“…Activation of the serine/threonine protein kinase activity of mTOR leads to phosphorylation of several substrates, including S6K1 and the translational repressor 4E-BP1. The role of these proteins in protein synthesis regulation has been reviewed extensively (4,20,30,32,39,40,48,55).…”

mentioning

confidence: 99%

Potential role of leucine metabolism in the leucine-signaling pathway involving mTOR

Lynch

Halle²,

Fujii³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

102

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Leucine has been shown to stimulate adipose tissue protein synthesis in vivo as well as leptin secretion, protein synthesis, hyper-plastic growth, and tissue morphogenesis in in vitro experiments using freshly isolated adipocytes. Recently, others have proposed that leucine oxidation in the mitochondria may be required to activate the mammalian target of rapamycin (mTOR), the cytosolic Ser/Thr protein kinase that appears to mediate some of these effects. The first irreversible and rate-limiting step in leucine oxidation is catalyzed by the branched-chain α-keto acid dehydrogenase (BCKD) complex. The activity of this complex is regulated acutely by phosphorylation of the E1α-subunit at Ser293 (S293), which inactivates the complex. Because the α-keto acid of leucine regulates the activity of BCKD kinase, it has been suggested as a potential target for leucine regulation of mTOR. To study the regulation of BCKD phosphorylation and its potential link to mTOR activation, a phosphopeptide-specific antibody recognizing this site was developed and characterized. Phospho-S293 (pS293) immunoreactivity in liver corresponded closely to diet-induced changes in BCKD activity state. Immunoreactivity was also increased in TREMK-4 cells after the induction of BCKD kinase by a drug-inducible promoter. BCKD S293 phosphorylations in adipose tissue and gastrocnemius (which is mostly inactive in vivo) were similar. This suggests that BCKD complex in epididymal adipose tissue from food-deprived rats is mostly inactive (unable to oxidize leucine), as is the case in muscle. To begin to test the leucine oxidation hypothesis of mTOR activation, the dose-dependent effects of orally administered leucine on acute activation of S6K1 (an mTOR substrate) and BCKD were compared using the pS293 antibodies. Increasing doses of leucine directly correlated with increases in plasma leucine concentration. Phosphorylation of S6K1 (Thr389, the phosphorylation site leading to activation) in adipose tissue was maximal at a dose of leucine that increased plasma leucine approximately threefold. Changes in BCKD phosphorylation state required higher plasma leucine concentrations. The results seem more consistent with a role for BCKD and BCKD kinase in the activation of leucine metabolism/oxidation than in the activation of the leucine signal to mTOR.

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mTOR inhibitors: An overview

Cited by 179 publications

References 102 publications

Therapeutic targets: MTOR and related pathways

Therapeutic targets: MTOR and related pathways

Methionine Sulfoximine Treatment and Carbon Starvation Elicit Snf1-independent Phosphorylation of the Transcription Activator Gln3 in Saccharomyces cerevisiae

Potential role of leucine metabolism in the leucine-signaling pathway involving mTOR

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