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Purity: ≥98%
WYE-125132 (also known as WYE 132) is a novel, highly potent, selective and ATP-competitive inhibitor of mTOR (mammalian target of rapamycin) with potential antitumor activity. It inhibits mTOR with an IC50 of 0.19 nM; It exhibits high selectivity for mTOR over PI3K and inhibits mTOR with an IC50 of 0.19 nM.
| Targets |
mTOR (IC50 = 0.19 nM); PI3Kα (IC50 = 1.179 μM); PI3Kδ (IC50 = 2.38 μM); hSMG1 (IC50 = 1.25 μM); mTORC1; mTORC2
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| ln Vitro |
WYE-125132 exhibits high selectivity over a panel of 230 protein kinases as well as potent and ATP-competitive inhibition of recombinant mTOR kinase with an IC50 of 0.19 nM. [1] With an IC50 range of 2 nM (LNCap) to 380 nM (HTC116), WYE-125132 exhibits a significant anti-proliferative activity in vitro against a panel of tumor cell lines. In addition, WYE-125132 promotes the cell cycle, induces apoptosis, and inhibits the synthesis of proteins and cell growth. [1] WYE-125132 results in a significant reduction in the synthesis of pre-tRNALeu by 72%, 80%, and 53% in actively proliferating cells of MG63, MDA361, and HEK293, respectively by inhibiting mTORC1. In addition, WYE-125132 is discovered to cause Maf1 (a negative regulator of Pol III transcription) to dephosphorylate and accumulate in the nucleus. [2]
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| ln Vivo |
WYE-125132 (5 mg/kg p.o.) produces significant antitumor activity and causes dose-dependent tumor growth delay in the PI3K/mTOR- and HER2-hyperactive MDA361 tumor model. In addition, WYE-125132 also shows potent antitumor efficacy in the PTEN-null glioma U87MG, non-small cell lung cancer H1975 and A549 models.[1]
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| Enzyme Assay |
mTOR enzyme assays via dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA), ATP matrix assays, and mTOR immune-complex kinase assays are performed as follows. Anti-FRAP/TOR (N-19) immunoprecipitates the endogenous TOR in LNCap cell lysate. 1 mL of lysis buffer is added to 1 mg of cell lysate, 4 g of antibody, and protein-G/A agarose.
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| Cell Assay |
Cell lines of MDA-MB-361, MDA-MB-231, MDA-MB-468, BT549, LNCap, A549, H1975, H157, H460, U87MG, A498, 786-O, HCT116, MG63, Rat1, HEK293, and HeLa are obtained from the American Type Culture Collection. The following describes cell growth assays and IC50 calculation. Cells are plated in 96-well culture plates at a density of 1000–3000 cells per well for a period of 24 hours and are then given various doses of WYE–125132 or DMSO to see how well the tumor cells grow. Three days later, the viability of the cells is assessed using the MTS assay method, which uses an assay kit and the kit assay procedure. Each treatment's impact is quantified as a percentage of control growth in comparison to cells that were grown in the same culture plate but had received DMSO. For the purpose of calculating IC50 values, inhibitor dose response curves are plotted.
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| Animal Protocol |
Mice: For mTOR biomarker studies, different tumors (400 mm3) grown subcutaneously in female nude mice are dosed with WYE-125132, a drug formulated with 5% ethanol, 2% Tween 80, and 5% polyethylene glycol-400, by a single intravenous or oral injection. Immunoblotting is done after preparing tumor lysates. Nude mice with the tumors U87MG, MDA361, H1975, A549, A498, or 786-O are staged and randomized into treatment groups (n=10) for efficacy studies. Mice receive oral doses of either the vehicle or WYE-125132 on a daily basis (5 days on, 2 days off) for up to four cycles. Temsirolimus/CCI-779 is administered intravenously once a week in the form of WYE-132. Bevacizumab is prepared in PBS and administered intravenously according to the clinical regimen (200 g/mouse; once per week). Monitoring and analysis of tumor growth is done.
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| References |
| Molecular Formula |
C27H33N7O4
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|---|---|
| Molecular Weight |
519.595425367355
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| Exact Mass |
519.2594
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| Elemental Analysis |
C, 62.41; H, 6.40; N, 18.87; O, 12.32
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| CAS # |
1144068-46-1
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| Related CAS # |
1144068-46-1
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| Appearance |
White solid powder
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| SMILES |
CNC(=O)NC1=CC=C(C=C1)C2=NC3=C(C=NN3C4CCC5(CC4)OCCO5)C(=N2)N6CC7CCC(C6)O7
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| InChi Key |
QLHHRYZMBGPBJG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H33N7O4/c1-28-26(35)30-18-4-2-17(3-5-18)23-31-24(33-15-20-6-7-21(16-33)38-20)22-14-29-34(25(22)32-23)19-8-10-27(11-9-19)36-12-13-37-27/h2-5,14,19-21H,6-13,15-16H2,1H3,(H2,28,30,35)
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| Chemical Name |
1-[4-[1-(1,4-dioxaspiro[4.5]decan-8-yl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazolo[3,4-d]pyrimidin-6-yl]phenyl]-3-methylurea
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| Synonyms |
WYE125132; WYE 125132; WYE-125132; WYE 132; WYE-132; WYE132
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~104 mg/mL (~200.2 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
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| Solubility (In Vivo) |
30% PEG400+0.5% Tween80+5% propylene glycol: 30mg/mL (Please use freshly prepared in vivo formulations for optimal results.)
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9246 mL | 9.6228 mL | 19.2456 mL | |
| 5 mM | 0.3849 mL | 1.9246 mL | 3.8491 mL | |
| 10 mM | 0.1925 mL | 0.9623 mL | 1.9246 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
WYE-132 is a potent and selective inhibitor of mTORC1 and mTORC2. Cancer Res. 2010, 70(2), 621-631. |
WYE-132 inhibits mTOR signaling and tumor growth in PI3K/AKT/mTOR-hyperactivated tumor models in vivo. |
WYE-132 antitumor efficacy in lung and renal tumor models. |
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