1223001-51-1 Usage
Description
Different sources of media describe the Description of 1223001-51-1 differently. You can refer to the following data:
1. Torin 2 is a potent and selective mTOR inhibitor with IC50 of 0.25 nM in p53?/? MEFs cell line; 800-fold greater selectivity for mTOR than PI3K and improved pharmacokinetic properties. Inhibition of ATM/ATR/DNA-PK with EC50 of 28 nM/35 nM/118 nM,in PC3 cell lines respectively.
2. Torin 2 is a potent and selective inhibitor of cellular mTOR activity (EC50 = 0.3 nM). It shows more than 800-fold selectivity for mTOR over PI3K (EC50 = 200 nM) and greater than 100-fold binding selectivity relative to 440 other protein kinases. Torin 2 has significantly improved bioavailability (54%), metabolic stability, and plasma exposure compared to torin 1 .
In vitro
Torin 2 has the same binding mode as PI3Kγ, V882 serves as a hinge binding point and in the inner hydrophobic pocket Y867, D841 and D964 provide three more hydrogen bonds with aminopyridine side chain analogous to Y2225, D2195 and D2357 of mTOR. Torin 2 inhibits mTORC1, thus activates TFEB by promoting its nuclear translocation with EC50 of 1.666 mM. Torin 2(< 50 nM) causes a significant reduction in viability of both MZ-CRC-1 and TT cells. Torin 2 (100 nM) exerts a significant reduction of migration of both MZ-CRC-1 and TT cells.
In vivo
Torin 2 exhibits >95% pharmacodynamic response and half-time of 11.7 min in the mouse liver microsome stability study. Torin 2 exhibits the best bioavailability (51%), short half-life (0.72 hours) and low clearance(19.6 mL/min/kg) in male Swiss albino mice following intravenous and oral administration. Torin 2(20mg/kg) ablates MYCN tumors with reduction in MYCN protein levels and induction of apoptosis in Th-MYCN mice.
Uses
Different sources of media describe the Uses of 1223001-51-1 differently. You can refer to the following data:
1. Torin2 has been used:to examine its effect on LC3B-II levels in BORCS5- KO cellsto determine its potent activity (IC50?less than 1 μM) against A2780-cis ovarian cancer cellsin western blot analysis
2. Torin 2 is a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer.
Biochem/physiol Actions
Torin2 is a highly potent and selective ATP-competitive mTOR inhibitor. Torin2 has an IC50 of 0.25 nM and 800-fold greater selectivity for mTOR than PI3K.
references
[1] liu q, wang j, kang s a, et al. discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl) phenyl) benzo [h][1, 6] naphthyridin-2 (1 h)-one (torin2) as a potent, selective, and orally available mammalian target of rapamycin (mtor) inhibitor for treatment of cancer. journal of medicinal chemistry, 2011, 54(5): 1473-1480.
Check Digit Verification of cas no
The CAS Registry Mumber 1223001-51-1 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,2,2,3,0,0 and 1 respectively; the second part has 2 digits, 5 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 1223001-51:
(9*1)+(8*2)+(7*2)+(6*3)+(5*0)+(4*0)+(3*1)+(2*5)+(1*1)=71
71 % 10 = 1
So 1223001-51-1 is a valid CAS Registry Number.
1223001-51-1Relevant articles and documents
Design, synthesis, and docking studies of New Torin2 analogs as potential ATR/mTOR kinase inhibitors
Shaik, Althaf,Bhakuni, Rashmi,Kirubakaran, Sivapriya
, (2018/05/04)
Targeting DNA damage and response (DDR) pathway has become an attractive approach in cancer therapy. The key mediators involved in this pathway are ataxia telangiectasia-mutated kinase (ATM) and ataxia telangiectasia-mutated, Rad3-related kinase (ATR). These kinases induce cell cycle arrest in response to chemo- and radio-therapy and facilitate DNA repair via their major downstream targets. Targeting ATP-binding site of these kinases is currently under study. Torin2 is a second generation ATP competitive mTOR kinase inhibitor (EC50 = 250 pmol/L) with better pharmacokinetic profile. Torin2 also exhibits potent biochemical and cellular activity against ATM (EC50 = 28 nmol/L) and ATR (EC50 = 35 nmol/L) kinases. In this study, eight new Torin2 analogs were designed and synthesized through multistep synthesis. All the synthesized compounds were characterized by NMR and mass analysis. The newly synthesized analogs were evaluated for their anti-cancer activity via CellTiter-Glofi assay. Additionally, compounds 13 and 14 also showed significant inhibition for ATR and mTOR substrates, i.e., p-Chk1 Ser 317 and p70 S6K Thr 389, respectively. Compounds 13 and 14 displayed promising anti-cancer activity with HCT-116 cell lines in the preliminary study. Further, a comparative model of ATR kinase was generated using the SWISS-MODEL server and validated using PROCHECK, ProSA analysis. Synthesized compounds were docked into the ATP-binding site to understand the binding modes and for the rational design of new inhibitors.
SOLUBLE MTOR COMPLEXES AND MODULATORS THEREOF
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Page/Page column 154, (2010/04/30)
The present invention relates to small molecule modulators of mTORCl and mT0RC2, syntheses thereof, and intermediates thereto. Such small molecule modulators are useful in the treatment of proliferative diseases (e.g., benign neoplasms, cancers, inflammatory diseases, autoimmune diseases, diabetic retinopathy) and metabolic diseases. Novel small molecules are provided that inhibit one or more of mTORCl, mT0RC2, and PI3K-related proteins. Novel methods of providing soluble mTORCl and mT0RC2 complexes are discussed, as well as methods of using the soluble complexes in a high- throughput manner to screen for inhibitory compounds.
