| CAS |
No.1223001-51-1 |
| 英文名称 |
Torin 2 |
| 分子式 |
C24H15F3N4O |
| 分子量 |
432.41 |
| 溶解性 |
Soluble in DMSO ≥2mg/mL(Need ultrasonic) |
| 纯度 |
≥98% |
| 外观(性状) |
White to light yellow Solid |
| 储存条件 |
Powder:2-8℃，2 years;Insolvent(母液):-20℃，6 months;-80℃，1 year |
| 运输条件 |
冷藏运输 |
| MDL |
MFCD18782652 |
| SMILES |
C1=CC(=CC(=C1)N2C(=O)C=CC3=CN=C4C=CC(=CC4=C32)C5=CN=C(C=C5)N)C(F)(F)F |
| InChIKey |
GUXXEUUYCAYESJ-UHFFFAOYSA-N |
| InChI |
InChI=1S/C24H15F3N4O/c25-24(26，27)17-2-1-3-18(11-17)31-22(32)9-6-16-13-29-20-7-4-14(10-19(20)23(16)31)15-5-8-21(28)30-12-15/h1-13H，(H2，28，30) |
| PubChem CID |
51358113 |
| 靶点 |
mTOR;DNA-PK |
| 通路 |
PI3K/Akt/mTOR;DNA Damage/DNA Repair |
| 背景说明 |
Torin 2 是一种 mTOR 抑制剂，Torin 2 还抑制 DNA-PK。 |
| 生物活性 |
Torin 2 is an mTOR inhibitor with EC50 of 0.25 nM for inhibiting cellular mTOR activity， and exhibits 800-fold selectivity over PI3K (EC50: 200 nM). Torin 2 also inhibits DNA-PK with an IC50 of 0.5 nM in the cell free assay. Torin 2 can suppress both mTORC1 and mTORC2.[1-4] |
| In Vitro |
Torin 2 针对一组脂质激酶进行进一步分析，mTOR、DNA-分别为 pK、p110γ、hVPS34、PI4Kβ、PI3K-C2β 和 PI3K-C2α。Torin 2 (Torin2) 具有 250 pM EC50 用于抑制细胞中的 mTOR，同时相对于抑制 PI3K 和大多数其他蛋白激酶保持 800 倍的细胞选择性[1]。Torin 2 (Torin2) 对 PIKK 家族激酶表现出有效的生化和细胞活性，包括 ATM (EC50 28 nM)、ATR (EC50 35 nM) 和 DNA-PK (EC50 118 nM)。Torin 2 有效抑制 Akt 的 T308，Akt 是 PDK1 的直接底物和 PI3K 的间接底物，EC50 小于 10 nM[2]。Torin-2 可以同时抑制 mTORC1 和 mTORC2[4]。 |
| In Vivo |
Torin2 表现出良好的生物利用度和暴露，并且在单剂量 20 mg/kg 后可以维持对肺和肝脏中 mTOR 活性的强烈抑制至少 6 小时。Torin 2 更容易大规模生产，并表现出改进的药代动力学特性，这应该使其能够用于体内实验[1]。Torin 2 强烈抑制 pS6K (T389) 和 p4EBP1 (T37/46) 并部分抑制 pAkt (T308)。用 25 mg/kg 的 AZD6244 处理小鼠可显著抑制 pERK。Torin 2 (40 mg/kg) 和 AZD6244 (25 mg/kg) 的联合给药表现出对所有药效学标志物的强烈抑制[2]。用 Torin 2 和雷帕霉素处理可诱导星形胶质细胞分泌 IL-6，并可能有助于减少 SCI 后的机械超敏反应。Torin1 和 Torin 2 处理增加了 IL-6 mRNA，表明 PI3K-mTOR 通路是星形胶质细胞中 IL-6 表达的负调节因子。重要的是，Torin 2 处理未显示任何细胞毒性，因为通过 TUNEL 测定或通过蛋白质印迹法检测裂解半胱天冬酶 3 未观察到细胞死亡迹象[3]。 |
| 细胞实验 |
HCT116 cells are treated with 100 nM Torin 2 or AZD8055 for 1 hour before they are thoroughly washed out by 3×PBS and 1×DMEM medium. Then cells are incubated in DMEM medium for indicated time before they are lysed and collected using M-PER. Protein concentrations are measured and equal amount of proteins are loaded. Experiments are repeated three times and one set of results[2]. |
| 动物实验 |
Mice[1] Six-week old male C57BL/6 mice are fasted overnight prior to Torin 2 treatment. The mice are treated with vehicle (for 10 h) or Torin 2 (20 mg/kg for 6h) via oral gavage and then re-fed 1 h prior to sacrifice (CO2 asphyxiation). Liver and lung are collected and frozen on dry ice. The frozen tissue is thawed on ice and lysed by sonication in tissue lysis buffer (50 mM HEPES， pH 7.4， 40 mM NaCl， 2 mM EDTA， 1.5 mM sodium orthovanadate， 50 mM sodium fluoride， 10 mM sodium pyrophosphate， 10 mM sodium β-glycerophosphate， 0.1% SDS， 1.0% sodium deoxycholate， and 1.0% Triton， supplemented with protease inhibitor cocktail tablets). The concentration of clear lysate is measured using the Bradford assay and samples are subsequently normalized by protein content and analyzed by SDS-PAGE and immunoblotting. Rats[3] Female rats (220 g) are group-housed 4 animals per cage， and kept on a 12-hour light/dark cycle with food and water ad libitum. Spinal cord injury is done with the Keck Center for Neurosciences impactor using a 10 g weight dropped from a height of 25 mm onto the dorsal surface of the exposed spinal cord. After recording BBB scores， withdrawal thresholds evoked by touch stimulus， and body weights for the first week post-injury， animals are divided into 5 treatment groups: na?ve (N=4)， sham (N=6)， vehicle (N=6)， Torin 2 (N=6)， and Torin 2+Rapamycin (N=8). Torin 2 alone (4 mg/kg) or in combination with Rapamycin (1.5 mg/kg) is administered orally by gavage once a day starting at day 15 after injury and ending at day 29. In sham operated rats only the laminectomy is performed. |
| 数据来源文献 |
[1]. Liu Q， et al. Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1，6]naphthyridin-2(1H)-one (Torin2) as a potent， selective， and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer. J Med Chem. 2011 Mar 10;54(5):1473-80.
[2]. Liu Q， et al. Characterization of Torin2， an ATP-competitive inhibitor of mTOR， ATM， and ATR. Cancer Res. 2013 Apr 15;73(8):2574-86.
[3]. Codeluppi S， et al. Interleukin-6 secretion by astrocytes is dynamically regulated by PI3K-mTOR-calcium signaling. PLoS One. 2014 Mar 25;9(3):e92649.
[4]. Wang X， et al. mTORC signaling in hematopoiesis. Int J Hematol. 2016 May;103(5):510-8. |
| 规格 |
1mg 5mg 10mg 50mg 100mg |
| 单位 |
瓶 |
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