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

mTOR (哺乳动物雷帕霉素靶蛋)

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

  • mTORC1

  • mTORC2

Cat. No. Product Name Effect Purity
  • HY-10219
    Rapamycin Inhibitor 99.94%
    Rapamycin (Sirolimus) 是一种有效且特异性的 mTOR 抑制剂,作用于 HEK293 细胞,抑制 mTORIC50 为 0.1 nM。Rapamycin 与 FKBP12 结合且抑制 mTORC1。Rapamycin 还是一种自噬 (autophagy) 激活剂,免疫抑制剂。
  • HY-10218
    Everolimus Inhibitor 99.10%
    Everolimus (RAD001) 是一种 Rapamycin 的衍生物,也是一种有效的,选择性的和口服活性的 mTOR1 抑制剂。Everolimus 与 FKBP-12 结合可产生免疫抑制复合物。Everolimus 抑制肿瘤细胞增殖并诱导细胞凋亡 (apoptosis) 和自噬 (autophagy)。Everolimus 具有有效的免疫抑制和抗癌活性。
  • HY-B0795
    MHY1485 Activator 99.86%
    MHY1485 是一种有效的细胞渗透性 mTOR 激活剂,靶向 mTOR 的 ATP 结构域。MHY 1485 通过抑制自噬体和溶酶体之间的融合来抑制自噬 (autophagy)。
  • HY-U00434
    3BDO Activator 99.91%
    3BDO 是一种新型 mTOR 激活剂,也能抑制自噬。
  • HY-50910
    Temsirolimus Inhibitor 99.56%
    Temsirolimus 是 mTOR 抑制剂,IC50 值为 1.76 μM。Temsirolimus 能激活自噬 (autophagy),在动物模型中防止心脏功能恶化。
  • HY-113038
    D-α-Hydroxyglutaric acid Inhibitor
    D-α-Hydroxyglutaric acid ((R)-2-Hydroxyglutarate) 是神经代谢疾病 D-2-羟基戊二酸尿症中积累的主要代谢产物。D-α-Hydroxyglutaric acid 是 α-酮戊二酸 (α-KG) 的弱竞争拮抗剂,可抑制多种 α-KG 依赖性双加氧酶 (dioxygenases),Ki 为 10.87 mM。D-α-Hydroxyglutaric acid 可增加活性氧 (ROS) 的产生。D-α-Hydroxyglutaric acid 还可结合并抑制 ATP 合酶并抑制 mTOR 信号传导。
  • HY-N0109
    Salidroside Activator 98.63%
    Salidroside 是一种脯氨酰内肽酶 (prolyl endopeptidase) 抑制剂。Salidroside 可通过激活 mTOR 信号缓解肿瘤恶病质小鼠模型中的恶病质症状。Salidroside 还能通过增强 PINK1/Parkin 介导的线粒体自噬来保护多巴胺能神经元。
  • HY-10474
    Torkinib Inhibitor 98.76%
    Torkinib (PP 242) 是一种选择性,ATP 竞争型的 mTOR 抑制剂,IC50 为 8 nM。PP242 抑制 mTORC1mTORC2IC50 分别为 30 nM 和 58 nM。
  • HY-N0486
    L-Leucine Activator >98.0%
    L-Leucine 是一种必需的支链氨基酸 (BCAA),可激活 mTOR 信号通路。
  • HY-100542
    D-α-Hydroxyglutaric acid disodium Inhibitor >98.0%
    D-α-Hydroxyglutaric acid disodium (Disodium (R)-2-hydroxyglutarate) 是神经代谢疾病 D-2-羟基戊二酸尿症中积累的主要代谢产物。D-α-Hydroxyglutaric acid disodium 是 α-酮戊二酸 (α-KG) 的弱竞争拮抗剂,可抑制多种 α-KG 依赖性双加氧酶 (dioxygenases),Ki 为 10.87 mM。D-α-Hydroxyglutaric acid disodium 可增加活性氧 (ROS) 的产生。D-α-Hydroxyglutaric acid disodium 还可结合并抑制 ATP 合酶并抑制 mTOR 信号传导。
  • HY-N0112
    Dihydromyricetin Inhibitor 99.79%
    Dihydromyricetin 是一种有效的二氢嘧啶酶 (dihydropyrimidinase) 抑制剂,IC50 为 48 μM。Dihydromyricetin 可通过抑制 mTOR 信号从而激活自噬。Dihydromyricetin 抑制 mTOR 复合体 (mTORC1/2) 形成。Dihydromyricetin 还是一种流感依赖 RNA 的 RNA 聚合酶抑制剂,IC50 为 22 μM。
  • HY-10372
    PP121 Inhibitor 99.08%
    PP121是多靶点激酶抑制剂,抑制 mTORDNK-PKVEGFR2SrcPDGFRIC50 值分别为10,60,12,14,2 nM。
  • HY-124798
    Rheb inhibitor NR1 Inhibitor >98.0%
    Rheb inhibitor NR1 是一种 Rheb 抑制剂,在 Rheb-IVK分析中,IC50 为 2.1 μM。Rheb inhibitor NR1 是一种选择性的 mTORC1 抑制剂。Rheb inhibitor NR1 抑制 S6K1 在 T389 位点磷酸化,并增加 AKT 在 S473 位点磷酸化。
  • HY-13334
    BGT226 maleate Inhibitor 99.76%
    BGT226 (NVP-BGT226 maleate) 是一种 PI3K (针对 PI3KαPI3KβPI3KγIC50分别是4 nM,63 nM,38 nM ) /mTOR 双抑制剂,对人头颈癌细胞具有较强的生长抑制活性。
  • HY-12036
    GSK1059615 Inhibitor >99.0%
    GSK1059615 是 PI3Kα/β/δ/γ 可逆的抑制剂,同时也抑制 mTORIC50 值分别为 0.4 nM/0.6 nM/2 nM/5 nM 和 12 nM。
  • HY-10683
    PKI-402 Inhibitor 99.79%
    PKI-402 是一种有效的 PI3KmTOR 抑制剂,抑制 PI3Kα, mTOR, PI3Kβ, PI3Kδ 和 PI3Kγ,IC50 分别为 2, 3, 7, 14 和 16 nM。
  • HY-15521
    ETP-46464 Inhibitor 98.01%
    ETP-46464 是一种有效的 mTORATR 抑制剂,IC50 分别为 0.6 和 14 nM。
  • HY-12763
    GNE-317 Inhibitor 99.31%
    GNE-317 是一种 PI3K/mTOR 抑制剂,能够穿过血脑屏障 (BBB)。
  • HY-12034
    WYE-354 Inhibitor 98.00%
    WYE-354 是一种 ATP 竞争性的 mTOR 抑制剂,IC50 为 5 nM。WYE-354 也抑制 PI3KαPI3KγIC50 分别为 1.89 μM 和 7.37 μM。WYE-354 抑制 mTORC1mTORC2。WYE-354 在体外能诱导自噬 (autophagy) 激活.
  • HY-114414
    HDACs/mTOR Inhibitor 1 Inhibitor 99.12%
    HDACs/mTOR Inhibitor 1 是组蛋白去乙酰酶抑制剂 (HDAC) 和哺乳动物雷帕霉素 (mTOR) 的双重抑制剂,有潜力用于恶性血液病的研究,其对 HDAC1、HDAC6、mTOR 和 PI3Kα 的 IC50 值分别为 0.19 nM、1.8 nM、1.2 nM 和 >500 nM。HDACs/mTOR Inhibitor 1 能够引起 G0/G1 期的细胞阻滞,诱导肿瘤细胞凋亡,在体内毒性较低。

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.

Isoform Specific Products

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