Torin 2 undergoes further profiling against a panel of lipid kinases, exhibiting IC50 values of 2.81 nM, 0.5 nM, 5.67 nM, 8.58 nM, 18.3 nM, 24.5 nM, and 28.1 nM for mTOR, DNA-pK, p110γ, hVPS34, PI4Kβ, PI3K-C2β, and PI3K-C2α, respectively. Torin 2 demonstrates a 250 pM EC50 for inhibiting mTOR in cells while maintaining an 800-fold cellular selectivity compared to inhibition of PI3K and most other protein kinases[1]. Torin 2 demonstrates strong biochemical and cellular activity against PIKK family kinases, such as ATM (EC50 28 nM), ATR (EC50 35 nM), and DNA-PK (EC50 118 nM). Additionally, Torin 2 potently inhibits T308 of Akt, which is a direct substrate of PDK1 and an indirect substrate of PI3Ks, with an EC50 of less than 10 nM[2]. Torin 2 has the capability to inhibit both mTORC1 and mTORC2[4].
体内研究
Torin 2 demonstrates favorable bioavailability and exposure, sustaining potent inhibition of mTOR activity in the lung and liver for at least six hours following a single dose of 20 mg/kg. Additionally, Torin 2 is easier to manufacture at scale and displays enhanced pharmacokinetic properties, facilitating its utilization in in vivo experiments[1].
Torin 2 effectively inhibits phosphorylation of S6K(T389) and 4EBP1(T37/46), and partially inhibits phosphorylation of Akt(T308). Administration of AZD6244 at 25 mg/kg to mice results in significant inhibition of ERK phosphorylation. Co-administration of Torin 2 (40 mg/kg) and AZD6244 (25 mg/kg) shows robust inhibition of all pharmacodynamic markers[2].
Administration of Torin 2 and Rapamycin leads to the secretion of IL-6 by astrocytes, potentially aiding in the alleviation of mechanical hypersensitivity following spinal cord injury (SCI). Treatment with Torin1 and Torin 2 enhances IL-6 mRNA levels, indicating that the PI3K-mTOR pathway acts as a negative regulator of IL-6 expression in astrocytes. Notably, Torin 2 treatment exhibits no cellular toxicity, as evidenced by the absence of cell death observed through TUNEL assay or detection of cleaved-caspase 3 by western blotting[3].
体外研究
Torin 2 undergoes further profiling against a panel of lipid kinases, exhibiting IC50 values of 2.81 nM, 0.5 nM, 5.67 nM, 8.58 nM, 18.3 nM, 24.5 nM, and 28.1 nM for mTOR, DNA-pK, p110γ, hVPS34, PI4Kβ, PI3K-C2β, and PI3K-C2α, respectively. Torin 2 demonstrates a 250 pM EC50 for inhibiting mTOR in cells while maintaining an 800-fold cellular selectivity compared to inhibition of PI3K and most other protein kinases[1].
Torin 2 demonstrates strong biochemical and cellular activity against PIKK family kinases, such as ATM (EC50 28 nM), ATR (EC50 35 nM), and DNA-PK (EC50 118 nM). Additionally, Torin 2 potently inhibits T308 of Akt, which is a direct substrate of PDK1 and an indirect substrate of PI3Ks, with an EC50 of less than 10 nM[2].
Torin 2 has the capability to inhibit both mTORC1 and mTORC2[4].
Torin 2 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
human PC3 cells
Function assay
Inhibition of PI3Kalpha in human PC3 cells expressing Akt1 S473D mutant assessed as phosphorylation of Akt Thr308 by immunoblotting, EC50=0.2 μM
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