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WYE-125132 (WYE-132)

ATP-competitive mTOR inhibitor, highly potent CAS# 1144068-46-1

WYE-125132 (WYE-132)

Catalog No. BCC4608----Order now to get a substantial discount!

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Chemical structure

WYE-125132 (WYE-132)

3D structure

Chemical Properties of WYE-125132 (WYE-132)

Cas No. 1144068-46-1 SDF Download SDF
PubChem ID 25260757 Appearance Powder
Formula C27H33N7O4 M.Wt 519.61
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 25 mg/mL (48.11 mM; Need ultrasonic)
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
SMILES CNC(=O)NC1=CC=C(C=C1)C2=NC3=C(C=NN3C4CCC5(CC4)OCCO5)C(=N2)N6CC7CCC(C6)O7
Standard InChIKey QLHHRYZMBGPBJG-UHFFFAOYSA-N
Standard InChI 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)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of WYE-125132 (WYE-132)

DescriptionWYE-125132 (WYE-132) is a highly potent, ATP-competitive inhibitor of mTOR with an IC50 value of 0.19 nM.
TargetsmTOR    
IC500.19 nM     

Protocol

Kinase Assay [1]
mTOR enzyme assays via dissociation-enhanced lanthanide fluorescent immunoassay, ATP matrix assays, and mTOR immune-complex kinase assays are performed. Assays of PI3Ks are performed. hSMG1 and ATR are assayed using glutathione S-transferase-p53 as a substrate, detected via DELFIA using an anti-P-p53 (S15) antibody. Assays of a panel of 230 protein kinases are performed[1].

Cell Assay [1]
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, HeLa and PC3MM2 are used. MDA361 cells are treated for 3 d with CCI-779 and WYE-125132 (0.1 nM, 1 nM, 10 nM,100 nM, 1000 nM 10μM and 100μM). Cell growth assays and IC50 determination are performed. For immunoblotting, cultured cells are treated as indicated. Total cell lysates are prepared using NuPAGE lithium dodecyl sulfate sample buffer and immunoblotted with various antibodies[1].

Animal Administration [1]
Mice[1] For mTOR biomarker studies, various tumors (400 mm3) grown s.c. in female nude mice are dosed by a single i.v. or oral injection with vehicle or WYE-125132 formulated in 5% ethanol, 2% Tween 80, and 5% polyethylene glycol-400. Tumor lysates are prepared and immunoblotted. For efficacy studies, nude mice bearing U87MG, MDA361, H1975, A549, A498, or 786-O tumors are staged and randomized into treatment groups (n=10). Mice are dosed orally with vehicle or WYE-125132 following qd x5 cycle regimen (5 d on, 2 d off) for up to four cycles. Temsirolimus/CCI-779 is formulated as WYE-125132 and dosed i.v. once weekly. Bevacizumab is formulated in PBS and dosed i.p. via its clinical regimen (200 μg/mouse; once weekly). Tumor growth is monitored and analyzed.

References:
[1]. Yu K, et al. Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2.Cancer Res. 2010 Jan 15;70(2):621-631.

WYE-125132 (WYE-132) Dilution Calculator

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Preparing Stock Solutions of WYE-125132 (WYE-132)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.9245 mL 9.6226 mL 19.2452 mL 38.4904 mL 48.113 mL
5 mM 0.3849 mL 1.9245 mL 3.849 mL 7.6981 mL 9.6226 mL
10 mM 0.1925 mL 0.9623 mL 1.9245 mL 3.849 mL 4.8113 mL
50 mM 0.0385 mL 0.1925 mL 0.3849 mL 0.7698 mL 0.9623 mL
100 mM 0.0192 mL 0.0962 mL 0.1925 mL 0.3849 mL 0.4811 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on WYE-125132 (WYE-132)

WYE-125132 (WYE-132) is highly potent, ATP-competitive, and specific inhibitor of mTOR kinase with IC50 value of 0.19±0.07nmol/L, >5000-fold selective versus PI3Ks [1].

WYE-125132 (WYE-132) has been reported to mTORC1-dependent phosphorylation of S6K (T389) and mTORC2-dependent phos-phorylation of AKT (S473) in immune-complex assay. In addition, in insulin-like growth factor-I(IGF-I)–induced Rat1, the PIK3CA mutant MDA361, or PTEN-null U87MG cells, WYE-125132 (WYE-132) has also been revealed to dose-dependently inhibit P-S6K(T389) and P-AKT(S473) with EC50 in low nanomolar range. Apart from these, WYE-125132 (WYE-132) has shown a potent anti-proliferative agent against MDA361, PC3MM2, U87MG, A549, and HCT116 cell lines. Moreover, WYE-125132 (WYE-132) has noted a stronger inhibition of protein synthesis and cell size in MDA361 and HEK293 cell lines [1].

References:
[1] Yu K1, Shi C, Toral-Barza L, Lucas J, Shor B, Kim JE, Zhang WG, Mahoney R, Gaydos C, Tardio L, Kim SK, Conant R, Curran K, Kaplan J, Verheijen J, Ayral-Kaloustian S, Mansour TS, Abraham RT, Zask A, Gibbons JJ. Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res. 2010 Jan 15;70(2):621-31. doi: 10.1158/0008-5472.CAN-09-2340. Epub 2010 Jan 12.

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References on WYE-125132 (WYE-132)

Requirement of the mTOR kinase for the regulation of Maf1 phosphorylation and control of RNA polymerase III-dependent transcription in cancer cells.[Pubmed:20233713]

J Biol Chem. 2010 May 14;285(20):15380-92.

The mammalian target of rapamycin (mTOR) regulates growth via promoting translation and transcription. Here, employing an mTOR active-site inhibitor WYE-125132 (WYE-132), we have performed quantitative phospho-proteomics and identified a Ser-75-containing phosphopeptide from Maf1, a known repressor of RNA polymerase III (Pol III) transcription. Treatment of cancer cells with WYE-132 or the rapamycin analog CCI-779 led to a rapid loss of the phosphorylation at Ser-75, whereas this effect was not seen in cells treated with cytotoxic agents or unrelated inhibitors. WYE-132-induced Maf1 dephosphorylation correlated with its accumulation in the nucleus and a marked decline in the cellular levels of pre-tRNAs. Depletion of cellular Maf1 via small interfering RNA increased basal pre-tRNA and rendered tRNA synthesis refractory to mTOR inhibitors. Maf1 mutant proteins carrying S75A alone or with S60A, T64A, and S68A (Maf1-S75A, Maf1-4A) progressively enhanced basal repression of tRNA in actively proliferating cells and attenuated amino acid-induced tRNA transcription. Gene alignment revealed conservation of all four Ser/Thr sites in high eukaryotes, further supporting a critical role of these residues in Maf1 function. Interestingly, mTOR inhibition led to an increase in the occupancy of Maf1 on a set of Pol III-dependent genes, with concomitant reduction in the binding of Pol III and Brf1. Unexpectedly, mTORC1 itself was also enriched at the same set of Pol III templates, but this association was not influenced by mTOR inhibitor treatment. Our results highlight a new and unique mode of regulation of Pol III transcription by mTOR and suggest that normalization of Pol III activity may contribute to the therapeutic efficacy of mTOR inhibitors.

Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2.[Pubmed:20068177]

Cancer Res. 2010 Jan 15;70(2):621-31.

The mammalian target of rapamycin (mTOR) is a major component of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway that is dysregulated in 50% of all human malignancies. Rapamycin and its analogues (rapalogs) partially inhibit mTOR through allosteric binding to mTOR complex 1 (mTORC1) but not mTOR complex 2 (mTORC2), an emerging player in cancer. Here, we report WYE-125132 (WYE-132), a highly potent, ATP-competitive, and specific mTOR kinase inhibitor (IC(50): 0.19 +/- 0.07 nmol/L; >5,000-fold selective versus PI3Ks). WYE-132 inhibited mTORC1 and mTORC2 in diverse cancer models in vitro and in vivo. Importantly, consistent with genetic ablation of mTORC2, WYE-132 targeted P-AKT(S473) and AKT function without significantly reducing the steady-state level of the PI3K/PDK1 activity biomarker P-AKT(T308), highlighting a prominent and direct regulation of AKT by mTORC2 in cancer cells. Compared with the rapalog temsirolimus/CCI-779, WYE-132 elicited a substantially stronger inhibition of cancer cell growth and survival, protein synthesis, cell size, bioenergetic metabolism, and adaptation to hypoxia. Oral administration of WYE-132 to tumor-bearing mice showed potent single-agent antitumor activity against MDA361 breast, U87MG glioma, A549 and H1975 lung, as well as A498 and 786-O renal tumors. An optimal dose of WYE-132 achieved a substantial regression of MDA361 and A549 large tumors and caused complete regression of A498 large tumors when coadministered with bevacizumab. Our results further validate mTOR as a critical driver for tumor growth, establish WYE-132 as a potent and profound anticancer agent, and provide a strong rationale for clinical development of specific mTOR kinase inhibitors as new cancer therapy.

Description

WYE-132 (WYE-125132) is a highly potent, ATP-competitive, and specific mTOR kinase inhibitor (IC50: 0.19±0.07 nM; >5,000-fold selective versus PI3Ks). WYE-132 (WYE-125132) inhibits mTORC1 and mTORC2.

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