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-15248
    GDC-0349
    		Inhibitor 99.10%
    GDC-0349 is a potent and selective ATP-competitive mTOR inhibitor with a Ki of 3.8 nM. GDC-0349 inhibits of both mTORC1 and mTORC2 complexes.
    GDC-0349
  • HY-16441
    Tegafur-gimeracil-oteracil potassium
    		Inhibitor 99.96%
    Tegafur-gimeracil-oteracil potassium (S-1; TS-1) is an orally active anticancer agent composed of Tegafur (HY-17400), Gimeracil (HY-17469), and Oteracil potassium (HY-17511). Tegafur-gimeracil-oteracil potassium inhibits the proliferation, migration and invasion of endometrial cancer cells and induces apoptosis by blocking the PI3K/AKT/mTOR signaling pathway. Tegafur-gimeracil-oteracil potassium can be used in research related to endometrial cancer and gastric cancer with peritoneal metastasis.
    Tegafur-gimeracil-oteracil potassium
  • HY-174406A
    MT-125 free base
    		Activator 98.67%
    MT-125 free base is a specific and well-tolerated inhibitor of non-muscle myosin IIA (Ki,NMIIA = 2.7 μM) and IIB (EC50 = 1.7 μM). MT-125 free base can pass through the blood-brain barrier. MT-125 free base induces ferroptosis and DNA damage by increasing the levels of reactive oxygen species (ROS) within tumor cells. MT-125 free base can enhance the PDGFR signaling pathway. MT-125 free base can be used for research on glioblastoma.
    MT-125 free base
  • HY-N2217
    Rotundic acid
    		Inhibitor 99.41%
    Rotundic acid is an orally effective triterpenoid with a Kd value of 51.3 µM for PTP1B. Rotundic acid downregulates the AKT/mTOR pro-survival pathway and modulates the MAPK pathway. Rotundic acid induces cell cycle S-phase arrest, DNA damage and apoptosis; it inhibits migration, invasion, angiogenesis and proliferation of cancer cells. Rotundic acid improves leptin sensitivity, regulates gut microbiota and reduces cellular senescence. Rotundic acid can be used in research related to hepatocellular carcinoma, obesity, aging, acute lung injury and type 2 diabetes.
    Rotundic acid
  • HY-126077
    MTI-31
    		Inhibitor 99.98%
    MTI-31 (LXI-15029) is a potent, orally active and highly selective inhibitor of mTORC1 and mTORC2. MTI-31 is selective for mTOR (Kd: 0.20 nM) versus PIK3CA, PIK3CB and PIK3G with >5,000 fold selectivity in mTOR binding assays. MTI-31 shows an IC50 of 39 nM for mTOR in LANCE assay of mTOR substrate phosphorylation with 100 μM ATP. MTI-31 can be used for the research of breast cancer.
    MTI-31
  • HY-N6843
    Arnicolide D
    		Inhibitor 99.69%
    Arnicolide D is a sesquiterpene lactone that can be isolated from Centipeda minima. Arnicolide D is cytotoxic to tumor cells and can induce cell cycle arrest, apoptosis, and oncosis in tumor cells. Arnicolide D has anti-tumor activity.
    Arnicolide D
  • HY-162143
    SKI-349
    		Inhibitor 99.48%
    SKI-349 is a dual-targeted inhibitor of sphingosine kinase 1/2 (SPHK1/2) and microtubule assembly (MDA). SKI-349 has anticancer activity. SKI-349 can inhibit the vitality, invasion, and AKT/mTOR signaling pathway of liver cells.
    SKI-349
  • HY-W142432
    Perfluoroundecanoic acid
    		Activator 99.85%
    Perfluoroundecanoic acid is a perfluoroalkyl substance (PFAS). Perfluoroundecanoic acid is an orally active oxidative stress inducer. Perfluoroundecanoic acid promotes macrophage M2 polarization, activates Wnt/β-catenin signaling and enhances β-catenin nuclear accumulation. Perfluoroundecanoic acid -induced M2 phenotype macrophage accelerates tumor progression in vitro and in vivo. Perfluoroundecanoic acid induces DNA damage, reproductive and pathophysiological dysfunctions via oxidative stress in male Swiss mice. Perfluoroundecanoic acid inhibits Leydig cell development in pubertal male rats via inducing oxidative stress and autophagy. Perfluoroundecanoic acid accelerates insulitis development in a mouse model of type 1 diabetes. Perfluoroundecanoic acid can be used for the study of ovarian cancer, type 1 diabetes and inflammation.
    Perfluoroundecanoic acid
  • HY-107365
    PQR530
    		Inhibitor 99.98%
    PQR530 is a potent, ATP-competitive, orally bioavailable and brain-penetrant dual pan-PI3K/mTORC1/2 inhibitor, with a subnanomolar Kd toward PI3Kα and mTOR (0.84 and 0.33 nM, respectively). Antitumor activity.
    PQR530
  • HY-100470
    NSC781406
    		Inhibitor 99.97%
    NSC781406 is a highly potent PI3K and mTOR inhibitor with an IC50 of 2 nM for PI3Kα.
    NSC781406
  • HY-10219G
    Rapamycin (GMP)
    		Inhibitor
    Rapamycin (Sirolimus) (GMP) is Rapamycin (HY-10219) produced by using GMP guidelines. GMP small molecules works appropriately as an auxiliary reagent for cell therapy manufacture. Rapamycin (Sirolimus; AY 22989) is a potent and specific blood-brain barrier-transmissible mTOR inhibitor with an IC50 of 0.1 nM in HEK293 cells. Rapamycin is a molecular glue that binds FKBP12 and mTOR proteins together, thereby inhibiting mTOR kinase activity. Rapamycin binds to FKBP12 and specifically acts as an allosteric inhibitor of mTORC1. Rapamycin is an autophagy activator, an immunosuppressant.
    Rapamycin (GMP)
  • HY-101955
    (2S,6S)-Hydroxynorketamine hydrochloride
    		Activator 99.30%
    (2S,6S)-Hydroxynorketamine hydrochloride is a neurorelaxant with potential antidepressant and analgesic effects. (2S,6S)-Hydroxynorketamine hydrochloride can activate the mTOR pathway, increase the phosphorylation level of downstream targets, and antagonize α7-nicotinic acetylcholine receptor (nAChR) to exert neuroactive properties.
    (2S,6S)-Hydroxynorketamine hydrochloride
  • HY-W338584
    Hydroxycitric acid tripotassium
    		Activator 98.0%
    Tripotassium hydroxycitrate is an orally active, multi-target, multi-bioactive organic acid. Tripotassium hydroxycitrate activates Nrf2 and its downstream molecule GPX4, increases glutathione levels, and thereby inhibits ferroptosis. Tripotassium hydroxycitrate activates the Nrf2/Keap1 and ACLY/NF-κB signaling pathways, upregulates the activities of antioxidant enzymes such as superoxide dismutase, reduces MDA content, thereby alleviating oxidative stress and renal tubular epithelial cell apoptosis, and improves pulmonary vascular and right ventricular remodeling. Tripotassium hydroxycitrate activates both the AMPK and mTORC1/S6K pathways, triggers the unfolded protein response, arrests the cancer cell cycle, and induces DNA fragmentation.
    Hydroxycitric acid tripotassium
  • HY-13806
    XL388
    		Inhibitor 99.57%
    XL388 is a highly potent and ATP-competitive mTOR inhibitor with an IC50 of 9.9 nM. XL388 simultaneously inhibits both mTORC1 and mTORC2.
    XL388
  • HY-N1163
    Tetrahydroalstonine
    		Activator 99.88%
    Tetrahydroalstonine ((-)-Tetrahydroalstonine) is an indole alkaloid and a selective α₂-adrenergic receptor antagonist. Tetrahydroalstonine exhibits certain neuroprotective effects. Tetrahydroalstonine can regulate autophagy-lysosomal function by activating the Akt/mTOR pathway, significantly reducing OGD/R-induced primary cortical neuronal injury.
    Tetrahydroalstonine
  • HY-11095
    NPS 2390
    		Inhibitor 99.90%
    NPS 2390 is an allosteric antagonist of calcium-sensing receptor (CaSR) and mGluR1/5. NPS 2390 inhibits the PI3K/Akt/mTOR signaling pathway, reduces hypoxia-induced intracellular calcium elevation, decreases the expression of autophagy (autophagy) proteins, regulates the expression of phenotypic marker proteins, and inhibits the proliferation of pulmonary artery smooth muscle cells. NPS 2390 attenuates the endogenous apoptosis (apoptosis) pathway, increases the expression level of Bcl-2, downregulates the expression levels of Bax, cytochrome c and caspase-3, alleviates cerebral edema and improves neurological function in rat models. NPS 2390 can be used in studies related to hypoxic pulmonary hypertension, traumatic brain injury, stroke and pain.
    NPS 2390
  • HY-11042
    GNE-477
    		Inhibitor 98.75%
    GNE-477 is a potent and efficacious dual PI3K (IC50=4 nM)/mTOR(Ki=21 nM) inhibitor.
    GNE-477
  • HY-131344
    mTOR inhibitor-8
    		Inhibitor 98.14%
    mTOR inhibitor-8 is an mTOR inhibitor and autophagy inducer. mTOR inhibitor-8 inhibits the activity of mTOR via FKBP12 and induces autophagy of A549 human lung cancer cells.
    mTOR inhibitor-8
  • HY-109179
    Itacnosertib
    		Inhibitor 99.06%
    Itacnosertib (TP-0184) is the inhibitor for FLT3, ACVR1 (ALK2, IC50=8 nM) and JAK2 (IC50=8540 nM). Itacnosertib exhibits anti-leukemic activity.
    Itacnosertib
  • HY-N1050
    Zederone
    		Inhibitor 99.61%
    Zederone is a sesquiterpene. Zederone inhibits ovarian cancer cell proliferation through mTOR/p70s6K signalling pathway. Zederone inhibits CYP activities with IC50s of 2.9 μM (CYP2B6), 9.2 μM (CYP2C9), 11,2 μM (CYP2C19) and >30 μM (CYP1A2 and CYP2D6). Zederone is hepatotoxic with LD50 value at 24 hours in mice of approximately 223 mg/kg and cytotoxic against the KG1a cell line. Zederone shows antibacterial activity against a number of multi-drug resistant and Methicillin (HY-121544)-resistant Staphylococcus aureus strain. Zederone shows cognition improving capacity and assists in the modulation of gut bacterial dysbiosis.
    Zederone
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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