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Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin.
TLDR
Three pyrazolopyrimidine ATP-competitive mTOR inhibitors are reported, with significant selectivity over phosphatidylinositol 3-kinase (PI3K) isofoms (>100-fold), to highlight mechanistic differentiation between rapalogs and mTOR kinase inhibitors in targeting cancer cell growth and survival and provide support for clinical development of mTORKinase inhibitors as new cancer therapy.
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Requirement of the mTOR Kinase for the Regulation of Maf1 Phosphorylation and Control of RNA Polymerase III-dependent Transcription in Cancer Cells
The mammalian target of rapamycin (mTOR) regulates growth via promoting translation and transcription. Here, employing an mTOR active-site inhibitor WYE-125132 (WYE-132), we have performed…
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Ammonia Derived from Glutaminolysis Is a Diffusible Regulator of Autophagy
TLDR
A direct link between glutamine (Gln) metabolism and autophagic activity in both transformed and nontransformed human cells is reported and treatments that alter intracellular glutamine concentrations or target glutamine metabolism may be possible strategies in cancer therapy.
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Targeting mTOR globally in cancer: Thinking beyond rapamycin
TLDR
Recent studies that highlight the emergence of rapamycin-resistant mTOR function in protein synthesis, cell growth, survival and metabolism are discussed, and it is shown that these rap amycin- resistant mTOR functions are profoundly inhibited by TKIs.
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Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2.
TLDR
The results further validate mTOR as a critical driver for tumor growth, establish WYE-132 as a potent and profound anticancer agent, and provide a strong rationale for clinical development of specific mTOR kinase inhibitors as new cancer therapy.
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A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis.
TLDR
It is reported that, at clinically relevant low micromolar concentrations, CCI-779 completely suppressed proliferation of a broad panel of tumor cells and suggests that high-dose CCi-779 inhibits mTOR signaling through an FKBP12-independent mechanism that leads to profound translational repression.
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Mammalian target of rapamycin: discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth.
Since the discovery of rapamycin, considerable progress has been made in unraveling the details of the mammalian target of rapamycin (mTOR) signaling network, including the upstream mechanisms that…
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Rolloamides A and B, cytotoxic cyclic heptapeptides isolated from the Caribbean marine sponge Eurypon laughlini.
TLDR
Two cyclic heptapeptides, rolloamides A and B, have been isolated from the Dominican marine sponge Eurypon laughlini and exhibits growth suppressive activity against a panel of histologically diverse cancer cell lines.
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Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a…
TLDR
A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea 26 (PKI-587).
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Lead optimization of N-3-substituted 7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors: discovery of PKI-402.
TLDR
In vitro and in vivo biomarker studies demonstrated the ability of 3 to shut down the PI3K/Akt pathway and induce apoptosis in cancer cells, validating suppression of PI3k/mTOR signaling as a potential anticancer therapy.
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