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
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
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/20860370
Curator's Comment: Known to be CNS penetrant in mouse. Human data not available
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL2221341 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20860370 |
4.3 nM [IC50] | ||
Target ID: P42345 Gene ID: 2475.0 Gene Symbol: MTOR Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/20860370 |
10.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
PubMed
Title | Date | PubMed |
---|---|---|
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 |
|
Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer. | 2010 Oct 14 |
|
mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. | 2011 Aug 5 |
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/20860370
Once daily administration of 20 mg/kg of torin 1 for 10 days in PTENnull glioblastoma mice U87MG xenograft model
Route of Administration:
Intraperitoneal
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19150980
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
Edited
Sat Dec 16 20:12:32 GMT 2023
by
admin
on
Sat Dec 16 20:12:32 GMT 2023
|
Record UNII |
K9HTV88VQZ
|
Record Status |
Validated (UNII)
|
Record Version |
|
-
Download
Name | Type | Language | ||
---|---|---|---|---|
|
Common Name | English | ||
|
Common Name | English |
Code System | Code | Type | Description | ||
---|---|---|---|---|---|
|
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
|
PRIMARY | |||
|
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 | |||
|
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 | |||
|
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 |
Related Record | Type | Details | ||
---|---|---|---|---|
|
TARGET -> INHIBITOR |
Significantly suppresses fluid endocytosis and bead/bacterial phagocytosis during TPA-induced differentiation, but not in undifferentiated THP-1 cells.
|
||
|
TARGET -> INHIBITOR |
|
Related Record | Type | Details | ||
---|---|---|---|---|
|
ACTIVE MOIETY |
|