Biological Activity
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.
In Vitro
Torin 2 is subject to further profiling against a panel of lipid kinases with IC50s 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 (Torin2) possesses a 250 pM EC50 for inhibiting mTOR in cells while maintaining 800-fold cellular selectivity relative to inhibition of PI3K and most other protein kinases[1]. Torin 2 (Torin2) exhibits potent biochemical and cellular activity against PIKK family kinases including ATM (EC50 28 nM), ATR (EC50 35 nM) and DNA-PK (EC50 118 nM). Torin 2 potently inhibits T308 of Akt, a direct substrate of PDK1 and an indirect substrate of PI3Ks, with an EC50 of less than 10 nM[2]. Torin-2 can suppress bothmTORC1 and mTORC2[4].
In Vivo
Torin 2 (Torin2) exhibits good bioavailability and exposure and can maintain strong inhibition of mTOR activity in lung and liver to at least six hours after a single dose of 20 mg/kg. Torin 2 is easier to produce on scale and exhibits improved pharmacokinetic properties which should enable it use in vivo experiments[1]. Torin 2 (Torin2) strongly suppresses pS6K(T389) and p4EBP1(T37/46) and partly suppresses pAkt(T308). Treatment of mice with AZD6244 at 25 mg/kg results in a profound inhibition of pERK. Combined administration of Torin 2 (40 mg/kg) and AZD6244 (25 mg/kg) demonstrates strong inhibition of all pharmacodynamics markers[2]. Treatment with Torin 2 (Torin2) and Rapamycin induces IL-6 secretion by astrocytes and may contribute to the reduction of mechanical hypersensitivity after SCI. Torin1 and Torin 2 treatment increases IL-6 mRNA, suggesting that the PI3K-mTOR pathway is a negative regulator of IL-6 expression in astrocytes. Importantly, Torin 2 treatment does not show any cell toxicity, as no signs of cell death are observed by TUNEL assay or by detection of cleaved-caspase 3 by western blotting[3].
References & source
Published experimental findings depend on the model and assay conditions. They do not guarantee equivalent performance in every application. For laboratory research use only.
