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

mTOR

Mammalian target of Rapamycin

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.

Cat. No. Product Name Effect Purity Chemical Structure
  • HY-N0047
    Polyphyllin I
    Inhibitor 99.89%
    Polyphyllin I is a bioactive constituent extracted from Paris polyphylla, has strong anti-tumor activity. Polyphyllin I is an activator of the JNK signaling pathway and is an inhibitor of PDK1/Akt/mTOR signaling. Polyphyllin I induces autophagy, G2/M phase arrest and apoptosis.
    Polyphyllin I
  • HY-19962
    Paxalisib
    Inhibitor 99.51%
    Paxalisib (GDC-0084) is a brain penetrant inhibitor of PI3K and mTOR, with Kis of 2 nM, 46 nM, 3 nM, 10 nM and 70 nM for PI3Kα PI3Kβ, PI3Kδ, PI3Kγ and mTOR, respectively.
    Paxalisib
  • HY-155864
    AJ2-30
    Inhibitor 99.92%
    AJ2-30 is a SLCl5A4 inhibitor. AJ2-30 inhibits endolysosomal TLR7-9-mediated mTOR activation. AJ2-30 blocks endogenous NOD signaling. AJ2-30 can be used in inflammation studies.
    AJ2-30
  • HY-15177
    PF-04691502
    Inhibitor 99.91%
    PF-04691502 is a potent and selective inhibitor of PI3K and mTOR. PF-04691502 binds to human PI3Kα, β, δ, γ and mTOR with Kis of 1.8, 2.1, 1.6, 1.9 and 16 nM, respectively.
    PF-04691502
  • HY-124760
    hSMG-1 inhibitor 11e
    Inhibitor 99.94%
    hSMG-1 inhibitor 11e is a potent and selective hSMG-1 kinase inhibitor with an IC50 of <0.05 nM. hSMG-1 inhibitor 11e shows >900-fold selectivity over mTOR (IC50 of 45 nM), PI3Kα/γ (IC50s of 61 nM and 92 nM) and CDK1/CDK2 (IC50s of 32 μM and 7.1 μM).
    hSMG-1 inhibitor 11e
  • HY-N0281
    Daphnetin
    Inhibitor 99.77%
    Daphnetin (7,8-dihydroxycoumarin), one coumarin derivative can be found in plants of the Genus Daphne, is a potent, oral active protein kinase inhibitor, with IC50s of 7.67 μM, 9.33 μM and 25.01 μM for EGFR, PKA and PKC in vitro, respectively. Daphnetin triggers ROS-induced cell apoptosis and induces cytoprotective autophagy by modulating the AMPK/Akt/mTOR pathway. Daphnetin has anti-inflammation activitity and inhibits TNF-α, IL-1β, ROS, and MDA production. Daphnetin has schizontocidal activity against malaria parasites. Daphnetin can be used for rheumatoid arthritis , cancer and anti-malarian research.
    Daphnetin
  • HY-P9933
    Dinutuximab
    Inhibitor ≥99.0%
    Dinutuximab (APN-311) is a chimeric human-mouse anti-GD2 monoclonal antibody. Dinutuximab can bind to GD2 on the cell surface, triggering antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity, and promoting tumor regression. Dinutuximab can inhibit the growth, invasion, and migration and induce apoptosis of tumor cells. Dinutuximab can be used in the research of tumors such as neuroblastoma and breast cancer.
    Dinutuximab
  • HY-50710
    KU-0063794
    Inhibitor 99.67%
    KU-0063794 is a potent and specific mTOR inhibitor, inhibiting both the mTORC1 and mTORC2 complexes with IC50s of 10 nM.
    KU-0063794
  • HY-116522
    AR420626
    98.29%
    AR420626 is a selective agonist of free fatty acid receptor 3 (FFAR3) (IC50=117 nM). AR420626 has anti-inflammatory, anticancer and antidiabetic activities. AR420626 improves neurogenic diarrhea by inhibiting nAChR mediated neural pathways. AR420626 inhibits the growth of HepG2 xenografts and inhibits the proliferation of hepatoma cells by inducing apoptosis. AR420626 also suppresses allergic asthma and eczema and has the ability to activate GPR41 to increase Ca2+ signal-mediated glucose uptake and improve diabetes.
    AR420626
  • HY-P1410B
    D-GsMTx4
    Inhibitor 99.59%
    D-GsMTx4 is a spider peptide and the D enantiomer of GsMTx4 (HY-P1410). D-GsMTx4 inhibits the mechanosensitive ion channel Piezo2. D-GsMTx4 inhibits [Ca2+]i elevation. D-GsMTx4 inhibits mTOR and PI3K-Akt signaling pathways. D-GsMTx4 inhibits mechanical allodynia and thermal hyperalgesia. D-GsMTx4 can be used in researches of mechanical stress, chronic pain and idiopathic pulmonary fibrosis.
    D-GsMTx4
  • HY-114384B
    Mefluleucine hydrochloride
    Activator ≥98.0%
    Mefluleucine (NV-513) hydrochloride, a leucine analog, is the first selective and orally active brain mTORC1 activator, binding to Sestrin2. Mefluleucine hydrochloride is used for antidepressant studies.
    Mefluleucine hydrochloride
  • HY-12513
    Samotolisib
    Inhibitor 99.27%
    Samotolisib (LY3023414) potently and selectively inhibits class I PI3K isoforms, DNA-PK, and mTORC1/2 with IC50s of 6.07 nM, 77.6 nM, 38 nM, 23.8 nM, 4.24 nM and 165 nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ, DNA-PK and mTOR, respectively. Samotolisib potently inhibits mTORC1/2 at low nanomolar concentrations.
    Samotolisib
  • HY-13246
    Apitolisib
    Inhibitor 99.29%
    Apitolisib (GDC-0980; GNE 390; RG 7422) is a selective, potent, orally bioavailable Class I PI3 kinase and mTOR kinase (TORC1/2) inhibitor with IC50s of 5 nM/27 nM/7 nM/14 nM for PI3Kα/PI3Kβ/PI3Kδ/PI3Kγ, and with a?Ki?of 17 nM for mTOR.
    Apitolisib
  • HY-12868
    Bimiralisib
    Inhibitor 98.62%
    Bimiralisib (PQR309) is a potent, brain-penetrant, orally bioavailable, pan-class I PI3K/mTOR inhibitor with IC50s of 33 nM, 451 nM, 661 nM, 708 nM and 89 nM for PI3Kα, PI3Kδ, PI3Kβ, PI3Kγ and mTOR, respectively. Bimiralisib is an mTORC1 and mTORC2 inhibitor.
    Bimiralisib
  • HY-N0486S9
    L-Leucine-d3
    Activator 99.93%
    L-Leucine-d3 is the deuterium labeled L-Leucine. L-Leucine is an essential branched-chain amino acid (BCAA), which activates the mTOR signaling pathway.
    L-Leucine-d<sub>3</sub>
  • HY-N0837
    Veratramine
    Inhibitor 99.84%
    Veratramine (NSC17821; NSC23880) is an orally active inhibitor of the PI3K/Akt/mTOR signaling pathway and a SIGMAR1 modulator. Veratramine induces autophagic apoptosis of tumor cells, arrests the cell cycle at the G0/G1 phase, and inhibits epithelial-mesenchymal transition (EMT)-related proteins to reduce tumor migration. Veratramine reduces spinal cord and sciatic nerve pathological damage in a neuropathy model by inhibiting SIGMAR1 binding to NMDAR and phosphorylation of NMDAR Ser896. Veratramine has anti-tumor proliferation, apoptosis induction, anti-inflammatory and neuroprotective activities, and can be used in the study of cancers such as liver cancer and osteosarcoma, as well as diabetic peripheral neuropathy.
    Veratramine
  • HY-N0486S1
    L-Leucine-13C
    Activator 99.4%
    L-Leucine-13C is the 13C-labeled L-Leucine. L-Leucine is an essential branched-chain amino acid (BCAA), which activates the mTOR signaling pathway.
    L-Leucine-<sup>13</sup>C
  • HY-N9481
    Lipoteichoic acid
    Inhibitor
    Lipoteichoic acid is an orally effect anti-inflammatory and antitumor agent. Lipoteichoic acid is a crucial immune molecule in Gram-positive bacteria that activates the complement system by inducing C3 and inhibiting CD55. Lipoteichoic acid regulates macrophage autophagy through the PI3K/Akt/mTOR pathway. Lipoteichoic acid induces lung damage in mice. Lipoteichoic acid inhibits the production of melanin.
    Lipoteichoic acid
  • HY-N0447
    8-Gingerol
    Modulator 99.82%
    8-Gingerol can be found in the rhizome of ginger (Z. officinale) and has oral bioactivity. It activates TRPV1, with an EC50 value of 5.0 µM. 8-Gingerol inhibits COX-2 and also suppresses the growth of H. pylori in vitro. Additionally, 8-Gingerol exhibits anticancer, antioxidant, and anti-inflammatory properties by inhibiting the epidermal growth factor receptor (EGFR) and modulating its downstream STAT3/ERK pathway to suppress the proliferation, migration, and invasion of colorectal cancer cells. 8-Gingerol also exerts immunosuppressive effects by inhibiting oxidative stress, inducing cell cycle arrest, promoting apoptosis, and regulating autophagy. Furthermore, 8-Gingerol has cardioprotective effects. 8-Gingerol is promising for research in the fields of cancer, infection, immunosuppression, and cardiovascular diseases.
    8-Gingerol
  • HY-16962
    CC-115
    Inhibitor 99.82%
    CC-115 is a potent and dual DNA-PK and mTOR kinase inhibitor with IC50s of 13 nM and 21 nM, respectively. CC-115 blocks both mTORC1 and mTORC2 signaling.
    CC-115
Cat. No. Product Name / Synonyms Application Reactivity

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.

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