A8312-5mg | Torin 1 [1222998-36-8] Clinisciences

Background

Torin 1, a tricyclic benzonaphthyridinone, is a potent and selective inhibitor of the mammalian target of rapamycin (mTOR) kinase, which is the catalytic subunit of two functionally distinct complexes and plays a pivotal role in the regulation of cell growth, proliferation and survival. Torin 1 directly inhibits the two mTOR-containing complexes, mTORC1 and mTORC2, through an ATP-competitive mechanism with half maximal inhibitory concentration IC50 of 2 nM and 10 nM respectively. Torin 1 has been found to impair cell growth and proliferation through a mechanism involving mTORC1 inhibition other than mTORC2 inhibition, in which the rapamycin-resistant functions of mTORC1 is suppressed.

References:
[1]Thoreen CC1, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem. 2009 Mar 20;284(12):8023-32. doi: 10.1074/jbc.M900301200. Epub 2009 Jan 15.
[2]Liu Q1, Chang JW, Wang J, Kang SA, Thoreen CC, Markhard A, Hur W, Zhang J, Sim T, Sabatini DM, Gray NS. Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo10[1,6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer. J Med Chem. 2010 Oct 14;53(19):7146-55. doi: 10.1021/jm101144f.

Product Citation

1. Jake W Carrasquillo Rodríguez, Onyedikachi Uche, et al. "Differential reliance of CTD-nuclear envelope phosphatase 1 on its regulatory subunit in ER lipid synthesis and storage." bioRxiv. 2023 Oct 13:2023.10.12.562096. PMID: 37873275
2. Schwartz, Hannah, et al. "In vitro Methods to Better Evaluate Drug Responses in Cancer." UMass Chan Medical School. September 8, 2022.
3. Jordan E Hollembeak, Michael A Model. "Stability of Intracellular Protein Concentration under Extreme Osmotic Challenge." Cells. 2021 Dec 14;10(12):3532. PMID: 34944039
4. Holly Merta, Jake W. Carrasquillo Rodríguez, et al. "Cell cycle regulation of ER membrane biogenesis protects against chromosome missegregation." Dev Cell. 2021 Dec 20;56(24):3364-3379.e10. PMID: 34852214
5. Bikash Ranjan Sahoo. "HOST CELL RESPONSES TO ZIKA VIRUS INFECTION." University of Nebraska, August, 2021.
6. Yilei Zhang, Robert V Swanda, et al. "mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation." Nat Commun. 2021 Mar 11;12(1):1589. PMID: 33707434
7. Bikash R. Sahoo, Aryamav Pattnaik, et al. "Mechanistic Target of Rapamycin (mTOR) Signaling Activation Antagonizes Autophagy to Facilitate Zika Virus Replication." J Virol 2020 Sep 2;JVI.01575-20. PMID: 32878890
8. Wang J, Chen Y, et al. "mTORC1-IRE1α pathway activation contributes to palmitate-elicited triglyceride secretion and cell death in hepatocytes." Exp Biol Med (Maywood). 2020;1535370220928276. PMID: 32436749
9. Martin-Hurtado A, Martin-Morales R, et al. "NRF2-dependent gene expression promotes ciliogenesis and Hedgehog signaling." Sci Rep. 2019 Sep 25;9(1):13896. PMID: 31554934
10. Zhang C, Duan Y, et al. "TFEB mediates immune evasion and resistance to mTOR inhibition of renal cell carcinoma via induction of PD-L1." Clin Cancer Res. 2019 Aug 5. pii: clincanres.0733.2019. PMID: 31383732
11. Rodríguez-Sánchez I, Schafer XL, et al. "The Human Cytomegalovirus UL38 protein drives mTOR-independent metabolic flux reprogramming by inhibiting TSC2." PLoS Pathog. 2019 Jan 24;15(1):e1007569. PMID: 30677091
12. Aline Pfefferle, Benedikt Jacobs, et al. "Intra-lineage Plasticity and Functional Reprogramming Maintain Natural Killer Cell Repertoire Diversity." bioRxiv. 2019 January 09. PMID: 30530705
13. Zhang Q, Presswalla F, et al. "A platform for assessing outer segment fate in primary human fetal RPE cultures." Exp Eye Res. 2018 Oct 15;178:212-222. PMID: 30336126
14. Admasu TD, Chaithanya Batchu K, et al. "Drug Synergy Slows Aging and Improves Healthspan through IGF and SREBP Lipid Signaling." Dev Cell. 2018 Oct 8;47(1):67-79.e5. PMID: 30269951
15. Wang K, Zhang T, et al."Identification of ANXA2 (annexin A2) as a specific bleomycin target to induce pulmonary fibrosis by impeding TFEB-mediated autophagic flux." Autophagy.2018;14(2):269-282. PMID: 29172997
16. Navid Koleini, Barbara E. Nickel, et al. "Fibroblast growth factor-2-mediated protection of cardiomyocytes from the toxic effects of doxorubicin requires the mTOR/Nrf-2/HO-1 pathway." Oncotarget.2017 August 24.
17. Jensen H, Potempa M, et al. "Cutting Edge: IL-2-Induced Expression of the Amino Acid Transporters SLC1A5 and CD98 Is a Prerequisite for NKG2D-Mediated Activation of Human NK Cells." J Immunol. 2017 Aug 7. pii: ji1700497. PMID: 28784848

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Chemical Properties

Physical Appearance	A solid
Storage	Desiccate at -20°C
M.Wt	607.64
Cas No.	1222998-36-8
Formula	C₃₅H₂₈F₃N₅O₂
Synonyms	Torin1;Torin-1
Solubility	insoluble in DMSO; insoluble in H2O; ≥2.42 mg/mL in EtOH with gentle warming and ultrasonic
Chemical Name	1-[4-(4-propanoylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]-9-quinolin-3-ylbenzo10[1,6]naphthyridin-2-one
SDF	Download SDF
Canonical SMILES	CCC(=O)N1CCN(CC1)C2=C(C=C(C=C2)N3C(=O)C=CC4=CN=C5C=CC(=CC5=C43)C6=CC7=CC=CC=C7N=C6)C(F)(F)F
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment [1]:
Cell lines	MEFs
Preparation method	Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37°C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20°C for several months.
Reaction Conditions	4 days; 1-6 h
Applications	250 nM Torin1 fully inhibits cell proliferation and induces a G1/S cell cycle arrest. Furthermore, 250 nM Torin1 decreases cell size to a larger degree than 50 nM rapamycin. In addtion, Torin1 disrupts mTORC1-dependent phenotypes more Completely than rapamycin.
Animal experiment [2]:
Animal models	U87-MG glioblastoma mice xenografts
Dosage form	Once daily IP dosing of 20 mg/kg
Preparation method	Dissolved at 25 mg/mL in 100% N-methyl-2-pyrrolidone
Applications	Torin1 treatment for 10 consecutive days leads to a greater than 99% inhibition of tumor growth. The tumor continues to grow after halt of the treatment, indicating that Torin1 is primarily cytostatic and that a substantial number of tumor cells are still viable during treatment.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: 1. Thoreen CC, Kang SA, Chang JW et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem. 2009 Mar 20;284(12):8023-32. 2. Liu Q, Chang JW, Wang J et al. Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benz o10[1,6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer. J Med Chem. 2010 Oct 14;53(19):7146-55.