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Details

Stereochemistry ACHIRAL
Molecular Formula C35H28F3N5O2
Molecular Weight 607.6243
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of Torin-1

SMILES

CCC(=O)N1CCN(CC1)C2=C(C=C(C=C2)N3C(=O)C=CC4=CN=C5C=CC(=CC5=C34)C6=CC7=CC=CC=C7N=C6)C(F)(F)F

InChI

InChIKey=AKCRNFFTGXBONI-UHFFFAOYSA-N
InChI=1S/C35H28F3N5O2/c1-2-32(44)42-15-13-41(14-16-42)31-11-9-26(19-28(31)35(36,37)38)43-33(45)12-8-24-20-40-30-10-7-22(18-27(30)34(24)43)25-17-23-5-3-4-6-29(23)39-21-25/h3-12,17-21H,2,13-16H2,1H3

HIDE SMILES / InChI

Molecular Formula C35H28F3N5O2
Molecular Weight 607.6243
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Torin 1 is a highly potent and selective ATP-competitive mTOR inhibitor discovered as a potential anticancer drug. It directly inhibits two functionally distinct complexes, mTORC1 and mTORC2, that coordinately promote cell growth, proliferation, and survival and impairs cell growth and proliferation to a far greater degree than rapamycin. Torin 1 is a picomolar inhibitor of mTORC1 enzymatic activity and single digit nanomolar inhibitor of cellular mTOR activity and has more than 800-fold selectivity between mTOR and PI3K. The pharmacokinetic properties of torin 1 were both in vitro and in vivo. It exhibited a short in vivo half-life and low oral bioavailability but displayed pharmacodynamic inhibition of both mTORC1 and mTORC2 outputs in lung and liver. Torin 1 dosed once a day at 20 mg/kg for 10 days demonstrated efficacy in a U87MG glioblastoma xenograft mouse model. Torin1 also caused lipin 1 nuclear translocation suggesting that lipin 1 cytoplasmic-nuclear relocalization responds to mTORC1 and not mTORC2 status. Torin 1 completely inhibited S106 lipin 1 phosphorylation and impaired S237 and S472 lipin 1 phosphorylation at prolonged exposure. Inhibition of mTORC1 in the liver significantly impairs SREBP function and makes mice resistant, in a lipin 1-dependent fashion, to the hepatic steatosis and hypercholesterolemia induced by a high fat and cholesterol diet. However, if potent mTORC1 inhibiting could be useful as potential treatments for metabolic syndrome has to be elucidated yet.

CNS Activity

Curator's Comment: Known to be CNS penetrant in mouse. Human data not available

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
4.3 nM [IC50]
Target ID: P42345
Gene ID: 2475.0
Gene Symbol: MTOR
Target Organism: Homo sapiens (Human)
10.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
PubMed

PubMed

TitleDatePubMed
The pharmacology of mTOR inhibition.
2009 Apr 21
An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1.
2009 Mar 20
mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway.
2011 Aug 5
Patents

Sample Use Guides

Once daily administration of 20 mg/kg of torin 1 for 10 days in PTENnull glioblastoma mice U87MG xenograft model
Route of Administration: Intraperitoneal
mTOR inhibition by Torin1 but not rapamycin prevents the proliferation of wild-type MEFs. MEF (p53-/-) cells were grown in the presence of 250 nm Torin1 for 4 days. Cell proliferation was measured in triplicate at indicated time points using the CellTiterGlo viability assay. Torin1 causes a G1/S cell cycle arrest in wild-type MEFs. MEF (p53-/-) cells were treated with 250 nm Torin1 for 48 h. Cells were then harvested, stained with propidium iodide, and analyzed by flow cytometry.
Substance Class Chemical
Created
by admin
on Sat Dec 16 20:12:32 GMT 2023
Edited
by admin
on Sat Dec 16 20:12:32 GMT 2023
Record UNII
K9HTV88VQZ
Record Status Validated (UNII)
Record Version
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Name Type Language
Torin-1
Common Name English
1-[4-[4-(1-Oxopropyl)-1-piperazinyl]-3-(trifluoromethyl)phenyl]-9-(3-quinolinyl)benzo[h]-1,6-naphthyridin-2(1H)-one
Common Name English
Code System Code Type Description
FDA UNII
K9HTV88VQZ
Created by admin on Sat Dec 16 20:12:33 GMT 2023 , Edited by admin on Sat Dec 16 20:12:33 GMT 2023
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WIKIPEDIA
Torin-1
Created by admin on Sat Dec 16 20:12:33 GMT 2023 , Edited by admin on Sat Dec 16 20:12:33 GMT 2023
PRIMARY
PUBCHEM
49836027
Created by admin on Sat Dec 16 20:12:33 GMT 2023 , Edited by admin on Sat Dec 16 20:12:33 GMT 2023
PRIMARY
CAS
1222998-36-8
Created by admin on Sat Dec 16 20:12:33 GMT 2023 , Edited by admin on Sat Dec 16 20:12:33 GMT 2023
PRIMARY
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