2. Signaling Pathways
  3. PI3K/Akt/mTOR
  4. mTOR

mTOR

Mammalian target of Rapamycin

mTOR

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mTOR (mammalian target of Rapamycin) is a protein that in humans is encoded by the mTOR gene. mTOR is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. mTOR belongs to the phosphatidylinositol 3-kinase-related kinase protein family. mTOR integrates the input from upstream pathways, including growth factors and amino acids. mTOR also senses cellular nutrient, oxygen, and energy levels. The mTOR pathway is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers. Rapamycin inhibits mTOR by associating with its intracellular receptor FKBP12. The FKBP12-rapamycin complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR, inhibiting its activity.

mTOR Isoform Specific Products:

mTOR Isoform Comparison
Cat. No. Product Name Effect Purity Chemical Structure
  • HY-10372
    PP121
    		Inhibitor 99.51%
    PP121 is a multi-targeted kinase inhibitor with IC50s of 10, 60, 12, 14, 2 nM for mTOR, DNK-PK, VEGFR2, Src, PDGFR, respectively.
    PP121
  • HY-50908
    Ridaforolimus
    		Inhibitor 99.75%
    Ridaforolimus (MK-8669) is a potent and selective mTOR inhibitor; inhibits ribosomal protein S6 phosphorylation with an IC50 of 0.2 nM in HT-1080 cells.
    Ridaforolimus
  • HY-128483
    Fusaric acid
    		Inhibitor 99.94%
    Fusaric acid is an orally active multi-pathway inhibitor with the activity of inducing oxidative stress and apoptosis. Fusaric acid can chelate divalent metal cations, damage mitochondrial membrane structure, and activate apoptosis-related proteases such as Caspase-3/7, -8, and -9. Fusaric acid also regulates Bax/Bcl-2 protein, inhibits fibrosis-related signaling pathways such as NF-κB, TGF-β1/SMADs, and PI3K/AKT/mTOR, and reduces collagen deposition. Fusaric acid is also a dopamine β-hydroxylase inhibitor, which reduces endogenous levels of norepinephrine and epinephrine in the brain, heart, spleen, and adrenal glands. Fusaric acid can play a role in myocardial fibrosis and improve cardiac hypertrophy in heart disease, and can also be used in the study of esophageal cancer and liver cancer.
    Fusaric acid
  • HY-12763
    GNE-317
    		Inhibitor 98.76%
    GNE-317 is a PI3K/mTOR inhibitor, is able to cross the blood-brain barrier (BBB).
    GNE-317
  • HY-N6626
    Pyraclostrobin
    		99.91%
    Pyraclostrobin is a highly effective and broad-spectrum strobilurin fungicide. Pyraclostrobin can induce oxidative DNA damage, mitochondrial dysfunction and autophagy through the activation of AMPK/mTOR signaling. Pyraclostrobin can be used to control crop diseases.
    Pyraclostrobin
  • HY-16956
    Onatasertib
    		Inhibitor 99.13%
    Onatasertib (CC-223) is a potent, selective, and orally bioavailable inhibitor of mTOR kinase, with an IC50 value for mTOR kinase of 16 nM. Onatasertib inhibits both mTORC1 and mTORC2.
    Onatasertib
  • HY-10219R
    Rapamycin (Standard)
    		Inhibitor
    Rapamycin (Standard) is the analytical standard of Rapamycin. This product is intended for research and analytical applications. Rapamycin (Sirolimus; AY 22989) is a potent and specific mTOR inhibitor with an IC50 of 0.1 nM in HEK293 cells. Rapamycin binds to FKBP12 and specifically acts as an allosteric inhibitor of mTORC1. Rapamycin is an autophagy activator, an immunosuppressant.
    Rapamycin (Standard)
  • HY-10683
    PKI-402
    		Inhibitor 99.17%
    PKI-402 is a selective, reversible, ATP-competitive inhibitor of PI3K, including PI3K-α mutants, and mTOR (IC50=2, 3, 7,14 and 16 nM for PI3Kα, mTOR, PI3Kβ, PI3Kδ and PI3Kγ).
    PKI-402
  • HY-16585
    VS-5584
    		Inhibitor 98.71%
    VS-5584 is a pan-PI3K/mTOR kinase inhibitor with IC50s of 16 nM, 68 nM, 42 nM, 25 nM, and 37 nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ and mTOR, respectively. VS-5584 simultaneously blocks mTORC2 as well as mTORC1.
    VS-5584
  • HY-10044
    WYE-132
    		Inhibitor 99.90%
    WYE-132 (WYE-125132) is a highly potent, ATP-competitive, and specific mTOR kinase inhibitor (IC50: 0.19±0.07 nM; >5,000-fold selective versus PI3Ks). WYE-132 (WYE-125132) inhibits mTORC1 and mTORC2.
    WYE-132
  • HY-115449
    Chromeceptin
    		p53 Inhibitor 99.80%
    Chromeceptin (94G6) is an IGF signaling pathway inhibitor. Chromeceptin suppresses IGF2 expression at mRNA and protein levels in hepatocyte and HCC cells. Chromeceptin inhibits the phosphorylation levels of AKT and mTOR.
    Chromeceptin
  • HY-18353
    mTOR inhibitor-3
    		Inhibitor 99.79%
    mTOR inhibitor-3 is a remarkably selective mTOR inhibitor with a Ki of 1.5 nM. mTOR inhibitor-3 suppresses mTORC1 and mTORC2 in cellular and in vivo pharmacokinetic (PK)/pharmacodynamic (PD) experiments.
    mTOR inhibitor-3
  • HY-139534
    ARI-1
    		Inhibitor 99.16%
    ARI-1 is a receptor tyrosine kinase-like orphan receptor 1 (ROR1) inhibitor. ARI-1 blocks the PI3K/AKT/mTOR signaling pathway in a ROR1-dependent manner. ARI-1 upregulates cleaved-PARP and p-P38. ARI-1 induces Apoptosis. ARI-1 has anticancer activity against non-small cell lung cancer.
    ARI-1
  • HY-N0486R
    L-Leucine (Standard)
    		Activator
    L-Leucine (Standard) is the analytical standard of L-Leucine. This product is intended for research and analytical applications. L-Leucine is an essential branched-chain amino acid (BCAA), which activates the mTOR signaling pathway.
    L-Leucine (Standard)
  • HY-15521
    ETP-46464
    		Inhibitor 99.54%
    ETP-46464 is an effective mTOR and ATR inhibitor with IC50s of 0.6 and 14 nM, respectively.
    ETP-46464
  • HY-13431
    KU-0060648
    		Inhibitor 99.62%
    KU-0060648 is a dual inhibitor of PI3K and DNA-PK with IC50s of 4 nM, 0.5 nM, 0.1 nM, 0.594 nM and 8.6 nM for PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ and DNA-PK, respectively.
    KU-0060648
  • HY-12036
    GSK1059615
    		Inhibitor 99.76%
    GSK1059615 is a dual inhibitor of PI3Kα/β/δ/γ (reversible) and mTOR with IC50 of 0.4 nM/0.6 nM/2 nM/5 nM and 12 nM, respectively.
    GSK1059615
  • HY-110228
    Metformin-d6 hydrochloride
    		Inhibitor 99.98%
    Metformin-d6 hydrochloride is a deuterium labeled Metformin hydrochloride. Metformin hydrochloride inhibits the mitochondrial respiratory chain in the liver, leading to AMPK activation and enhancing insulin sensitivity, and can be used in the study of type 2 diabetes. Metformin hydrochloride also inhibits liver oxidative stress, nitrosative stress, inflammation, and apoptosis caused by liver ischemia/reperfusion injury. In addition, metformin hydrochloride regulates the expression of autophagy-related proteins by activating AMPK and inhibiting the mTOR signaling pathway, thereby inducing tumor cell autophagy and inhibiting the growth of renal cell carcinoma in vitro and in vivo.
    Metformin-d<sub>6</sub> hydrochloride
  • HY-Y0396
    N-Hydroxyphthalimide
    		Inhibitor 99.89%
    N-Hydroxyphthalimide is a blocking agent and catalyst. N-Hydroxyphthalimide promotes oxidation reactions by generating PINO free radicals and activating hydrogen atom transfer processes. N-Hydroxyphthalimide reduces the expression of anti-apoptotic proteins Survivin and Bcl-xL and activates caspase 9 and caspase 3. N-Hydroxyphthalimide induces Apoptosis. N-Hydroxyphthalimide inhibits the phosphorylation of mTOR (Ser2448, Ser2481) and Akt (Ser473). N-Hydroxyphthalimide has anticancer effects against breast and colon cancer.
    N-Hydroxyphthalimide
  • HY-146751
    PI3K/Akt/mTOR-IN-2
    		Inhibitor 99.93%
    PI3K/Akt/mTOR-IN-2 is a PI3K/AKT/mTOR pathway inhibitor. PI3K/Akt/mTOR-IN-2 possess anti-cancer effects and selectivity against MDA-MB-231 cells with IC50 value of 2.29 μM. PI3K/Akt/mTOR-IN-2 can induce cancer cell cycle arrest and apoptosis.
    PI3K/Akt/mTOR-IN-2
Cat. No. Product Name / Synonyms Application Reactivity
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Download mTOR Signaling Pathway Map.

The mammalian target of rapamycin (mTOR) signaling pathway integrates both intracellular and extracellular signals and serves as a central regulator of cell metabolism, growth, proliferation and survival[1]. mTOR is the catalytic subunit of two distinct complexes called mTORC1 and mTORC2. mTORC1 comprises DEPTOR, PRAS40, RAPTOR, mLST8, mTOR, whereas mTORC2 comprises DEPTOR, mLST8, PROTOR, RICTOR, mSIN1, mTOR[2]. Rapamycin binds to FKBP12 and inhibits mTORC1 by disrupting the interaction between mTOR and RAPTOR. mTORC1 negatively regulates autophagy through multiple inputs, including inhibitory phosphorylation of ULK1 and TFEB. mTORC1 promotes protein synthesis through activation of the translation initiation promoter S6K and through inhibition of the inhibitory mRNA cap binding 4E-BP1, and regulates glycolysis through HIF-1α. It promotes de novo lipid synthesis through the SREBP transcription factors. mTORC2 inhibits FOXO1,3 through SGK and Akt, which can lead to increased longevity. The complex also regulates actin cytoskeleton assembly through PKC and Rho kinase[3]. 

 

Growth factors: Growth factors can signal to mTORC1 through both PI3K-Akt and Ras-Raf-MEK-ERK axis. For example, ERK and RSK phosphorylate TSC2, and inhibit it.

 

Insulin Receptor: The activated insulin receptor recruits intracellular adaptor protein IRS1. Phosphorylation of these proteins on tyrosine residues by the insulin receptor initiates the recruitment and activation of PI3K. PIP3 acts as a second messenger which promotes the phosphorylation of Akt and triggers the Akt-dependent multisite phosphorylation of TSC2. TSC is a heterotrimeric complex comprised of TSC1, TSC2, and TBC1D7, and functions as a GTPase activating protein (GAP) for the small GTPase Rheb, which directly binds and activates mTORC1. mTORC2 primarily functions as an effector of insulin/PI3K signaling. 

 

Wnt: The Wnt pathway activates mTORC1. Glycogen synthase kinase 3β (GSK-3β) acts as a negative regulator of mTORC1 by phosphorylating TSC2. mTORC2 is activated by Wnt in a manner dependent on the small GTPase RAC1[4].

 

Amino acids: mTORC1 senses both lysosomal and cytosolic amino acids through distinct mechanisms. Amino acids induce the movement of mTORC1 to lysosomal membranes, where the Rag proteins reside. A complex named Ragulator, interact with the Rag GTPases, recruits them to lysosomes through a mechanism dependent on the lysosomal v-ATPase, and is essential for mTORC1 activation. In turn, lysosomal recruitment enables mTORC1 to interact with GTP-bound RHEB, the end point of growth factor. Cytosolic leucine and arginine signal to mTORC1 through a distinct pathway comprised of the GATOR1 and GATOR2 complexes.    

 

Stresses: mTORC1 responds to intracellular and environmental stresses that are incompatible with growth such as low ATP levels, hypoxia, or DNA damage. A reduction in cellular energy charge, for example during glucose deprivation, activates the stress responsive metabolic regulator AMPK, which inhibits mTORC1 both indirectly, through phosphorylation and activation of TSC2, as well as directly through the phosphorylation of RAPTOR. Sestrin1/2 are two transcriptional targets of p53 that are implicated in the DNA damage response, and they potently activate AMPK, thus mediating the p53-dependent suppression of mTOR activity upon DNA damage. During hypoxia, mitochondrial respiration is impaired, leading to low ATP levels and activation of AMPK. Hypoxia also affects mTORC1 in AMPK-independent ways by inducing the expression of REDD1, the protein products of which then suppress mTORC1 by promoting the assembly of TSC1-TSC2[2].

 

Reference:

[1]. Laplante M, et al.mTOR signaling at a glance.J Cell Sci. 2009 Oct 15;122(Pt 20):3589-94. 
[2]. Zoncu R, et al. mTOR: from growth signal integration to cancer, diabetes and ageing.Nat Rev Mol Cell Biol. 2011 Jan;12(1):21-35. 
[3]. Johnson SC, et al. mTOR is a key modulator of ageing and age-related disease.Nature. 2013 Jan 17;493(7432):338-45.
[4]. Shimobayashi M, et al. Making new contacts: the mTOR network in metabolism and signalling crosstalk.Nat Rev Mol Cell Biol. 2014 Mar;15(3):155-62.

mTOR Isoform Comparison

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