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 细胞实验
Cell Line
Concentration
Treated Time
Description
References
NRVMs cells
50 nM
3 h
Activated autophagy and increased LC3-II protein levels
Autophagy. 2021 Oct;17(10):3124-3139.
HCT-116
100 nM
1 h
To evaluate the inhibitory effect of Torin2 on mTORC1 and mTORC2 activity.
Cancer Res. 2013 Apr 15;73(8):2574-86.
AG01522
100 nM
24 h
To evaluate the sensitivity of Torin2 to IR treatment.
Cancer Res. 2013 Apr 15;73(8):2574-86.
HEK293LU cells
50 nM
3 h
Activated autophagy and increased the number of GFP-LC3 puncta
Autophagy. 2021 Oct;17(10):3124-3139.
TM3 cells
10 μM
12 h
Torin 2 treatment increased LC3BII form and reduced intracellular mutant myocilin and p62 accumulation, indicating enhanced autophagic flux.
JCI Insight. 2021 Mar 8;6(5):e143359.
Rice ZH11 protoplasts
85 µM
4 h
To detect the phosphorylation level of OsS6K1 T464, results showed that the phosphorylation level of OsS6K1 T464 in ZH11 was significantly increased after sucrose treatment, while there was no significant change in nin8.
iScience. 2024 Dec 9;28(1):111555.
NIH-3T3 cells
150 nM
24 h
Torin inhibits phosphorylation of S6 and 4EBP1, and suppresses expression of GFP in wild type Fgf10 reporters but not in mutant Fgf10 reporters.
Cell Rep. 2014 Mar 13;6(5):818-26.
canine MM cells (M1, M5, M2, M3, and Jones)
10 μM to 0.125 nM
72 h
To evaluate the cytotoxicity of Torin 2 in combination with trametinib, results showed that the combination significantly reduced cell survival.
Mol Cancer Ther. 2020 Nov;19(11):2308-2318.
human cutaneous melanoma cells (WM3311, WM2032, WM853–2, WM858)
10 μM to 0.125 nM
72 h
To evaluate the cytotoxicity of Torin 2 in combination with trametinib, results showed that the combination significantly reduced cell survival.
Mol Cancer Ther. 2020 Nov;19(11):2308-2318.
bladder cancer cells
500 nM
3, 6, 9, or 24 h
Validate the efficacy of Torin 2 in cellular systems, confirming its induction of autophagy and reduction of GPX4 levels
Cell Death Dis. 2021 Oct 29;12(11):1028.
HaCaT cells
50 nM
1 h
Torin 2 treatment increased TRAIL expression, and this increase remained significant after UVB irradiation. Knockdown of FOXO3a reversed the increase in TRAIL expression induced by Torin 2.
Cell Signal. 2018 Dec;52:35-47.
A431 cells
50 nM
1 h
In A431 cells, Torin 2 treatment similarly increased UVB-induced apoptosis, and TRAIL knockdown did not reverse this effect.
Cell Signal. 2018 Dec;52:35-47.
Torin 2 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Tg-MYOCY437H mice
Topical ocular administration
100 μM
Twice daily for 7 days
Torin 2 treatment significantly reduced IOP in Tg-MYOCY437H mice and decreased myocilin and p62 accumulation in mouse TM tissues.
JCI Insight. 2021 Mar 8;6(5):e143359.
Mice
Inducible mutant Kras lung cancer model
Oral
10 mg/kg
Once daily for one week
To evaluate the inhibitory effect of MK-1775 combined with Torin 2 on KRAS-mutant lung cancer
Leukemia. 2015 Jan;29(1):27-37.
Mice
KRAS-driven lung cancer model
Oral
40 mg/kg
Once daily for 4 weeks
To evaluate the anti-tumor efficacy of Torin2 alone or in combination with the MEK inhibitor AZD6244 in a KRAS-driven lung cancer model.
Cancer Res. 2013 Apr 15;73(8):2574-86.
Mice
Canine MM xenograft model
Oral
40, 60, and 80 mg/kg
Daily administration for several days
To evaluate the efficacy and toxicity of Torin 2 in a canine MM xenograft model, results showed that Torin 2 inhibited tumor growth at therapeutic doses but caused weight loss in mice.
搜索
