Description
Torin1 (1222998-36-8) is a potent and selective ATP-competitive mTOR inhibitor, IC50=2 and 10 nM for mTORC1 and mTORC2 respectively.1,2 Active in vivo at inhibition of mTOR-mediated effects in mice (20 mg/kg).2 Induces autophagy.3 Torin 1-mediated enhancement of TFEB-mediated autophagy alleviates neuronal death in oxidative stress-induced disease models.4 Downregulates NGF expression in RSC96 cells.5
Chemical Properties
White Solid
Uses
Torin 1 is a potent and selective mTOR inhibitor (IC50 = 2 - 10 nM for mTORC1 and mTORC2). Displays 200-fold selectivity for mTOR over DNA-PK, ATM and hVps34.
Definition
ChEBI: Torin 1 is a member of the class of pyridoquinolines that is 9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2-one bearing an additional 4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl substituent at position 1. It is a potent inhibitor of mTOR and exhibits anti-cancer properties. It has a role as a mTOR inhibitor and an antineoplastic agent. It is a N-acylpiperazine, a N-arylpiperazine, an organofluorine compound, a pyridoquinoline and a member of quinolines.
General Description
A cell-permeable pyridinonequinoline derivative that acts as a highly potent, ATP-competitive inhibibitor against mTOR and DNA-PK (IC
50 = 4.32 and 6.34 nM, respectively, in cell-free kinase assays), inhibiting class I (IC
50 =171, 250, and 564 nM, respectively, against P110γ, P110α/P85α, and P110δ/P85α, respectively), class II (IC
50 =176 and 564 nM, respectively, against C2α, and C2β, respectively), and class III (IC
50 = 533 nM against hVPS34) PI 3-K only at much higher concentrations. Effectively inhibits mTORC1-mediated S6K1 Thr389 phosphorylation in MEF cultures (IC
50 = 2 nM)
in vitro, as well as mTORC2-mediated Akt Ser473 and mTORC1-dependent S6 Ser235/236 phosphorylations in murine lung and liver
in vivo (up to 6 h after single i.p. dose at 20 mg/kg). Despite its poor
in vivo stability (T
1/2 = 4.52 h in mice; 10 mg/kg i.p.), Torin1 is reported to completely suppress U87MG-derived tumor expansion in mice when administered via daily i.p. at a high dosage of 200 mg/kg. Also reported to effectively inhibit cellular mTORC1 functionalities known to be rapamycin-resistant (Cat. Nos.
553210,
553211, and
553212).
Biochem/physiol Actions
Cell permeable: yes
Background
Torin 1 is a potent and selective ATP-competitive mTOR inhibitor. Researchers have shown that Torin 1 inhibits mTORC1 and mTORC2 in cell-free kinase assays with IC50 values of 2 nM and 10 nM, respectively. Torin 1 displays nearly 1000-fold selectivity for mTOR over PI3 Kinase, 200-fold selectivity over ATM, DNA-PK, and hVps34, and does not significantly inhibit a panel of 353 serine/threonine, tyrosine, and lipid kinases at 10 μM. Torin 1 has also been shown to cause cell cycle arrest via a rapamycin-resistant mechanism independent of mTORC2. Torin 1 treatment of cells leads to the dephosphorylation of mTOR downstream targets including p70 S6 kinase, S6 Ribosomal Protein, and 4E-BP1. Activation and nuclear translocation of TFEB by Torin 1 inhibition of mTORC1 has also been observed.
References
1.Thoreen et al. (2009), An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1; J. Biol. Chem., 284 8023
2.Liu et al. (2010), Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinoline-3-yl)benzo[h][1,6]naphthyridine-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer; J. Med. Chem., 53 7146
3.Giulitti et al. (2021), Anti-tumor Effect of Oleic Acid in Hepatocellular Carcinoma Cell Lines via Autophagy Reduction; Cell Dev. Biol., 9 629182
4.Zhuang et al. (2020), Pharmacological enhancement of TFEB-mediated autophagy alleviated neuronal death in oxidative stress-induced Parkinson’s disease models; Cell Death Dis., 11 128
5.Cheng et al. (2018), DNMT1, a Novel Regulator Mediating mTORC1/mTORC2 Pathway-induced NGF Expression in Schwann Cells; Neurochem. Res, 43 2141
