生物活性

• 靶点

  mTORC1 IC50:2nM

  mTORC2 IC50:10nM

• 描述The mammalian target of rapamycin (mTOR) pathway is considered a major regulator of cell growth. The mTOR serine/threonine kinase is the founding component of the pathway with catalytic subunit of two functionally distinct protein complexes, mTORC1 and mTORC2. Torin1 is a potent inhibitor of mTORC1/2 with IC50s of 2 nM/10 nM. MEFs were treated with increasing amounts of Torin1 or the dual mTOR/PI3K inhibitors PI-103 and NVP-BEZ235, and the activity of each complex was determined by monitoring the phosphorylation status of S6K at Thr-389 and Akt at Ser-473, mTORC1 and mTORC2 substrates, respectively. And the cellular IC50 of Torin1 for PI3K to be 1.8 μM in mLST8-null MEFs. When screened Torin1 at a concentration of 10 μm against a panel of 353 diverse kinases, no indication of significant off-target effects was found. Besides, 250 nM Torin1 completely inhibited proliferation and caused a G1/S cell cycle arrest as well as decreased cell size to a greater degree than 50 nM rapamycin. NT secretion was noted to be increased at 3 and 24 h after 250 nM torin1 treatment while decreased Akt (S473) phosphorylation, phosphorylation of p70S6K(T389) as well as 4E-BP1(T37/46) was also inhibited. c-Jun and ERK1/2 activity were also increased in BON cells in the presence of torin1, suggesting that ERK/c-Jun signaling plays a role in the mTORC1-regulated NT gene expression. Such an induction of c-Jun and ERK1/2 expression can be inhibited by PD98059. Treated Hep3B cells with rapamycin (20 nM) or torin1 (250 nM) for 24 h, expression of both phosphorylated and total c-Jun was increased in a time-dependent fashion and induction of c-Jun and ERK1/2 phosphorylation was also noted in Hep3B cells. The inhibition of eIF4F assembly by asTORi could be largely mediated by 4E-BPs. Torin1 impaired translation to a greater extent in wild-type than in 4E-BP DKO MEFs. Torin1 had no effect on transcription or mRNA export, as judged by the unaltered cytoplasmic levels of cyclin D3, VEGF, and ODC mRNAs, and it specifically inhibited ribosome recruitment of eIF4E-sensitive mRNAs, as it had no impact on the polysome loading of eIF4E-insensitive β actin and GAPDH mRNAs.
• 作用机制Torin 1 is an ATP-competitive inhibitor.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  697	-	Growth Inhibition Assay	-	IC50=0.00634 μM	SANGER
  8-MG-BA	-	Growth Inhibition Assay	-	IC50=0.04629 μM	SANGER
  A101D	-	Growth Inhibition Assay	-	IC50=0.0265 μM	SANGER

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• 动物研究
  剂量	Mice: 1 mg/kg[3] (i.v.), 10 mg/kg[3] (i.p./p.o.), 20 mg/kg[3] (i.p.)
  给药途径	i.v., i.p., p.o.
  动物药代数据	Animal Nude mice[3] Dose 1 mg/kg (i.v.) 10 mg/kg (p.o. or i.p.) MRT 0.43 h (i.v.) 1.51 h (p.o.) F 5.49% (p.o.) T1/2 0.5 h (i.v.) 0.79 h (p.o.) 4.52 h (i.p.) Tmax 0.25 h (p.o.) 0.08 h (i.p.) Vss 0.59 L/kg (i.v.) Cmax 2757 ng/ml (i.v.) 223 ng/ml (p.o.) 5121 ng/ml (i.p.) CL 23.0 ml/min/kg (i.v.) AUC 720 h·ng/ml (i.v.) 396 h·ng/ml (p.o.) 5718 h·ng/ml (i.p.)