WYE-354

MTOR inhibitor,potent,ATP-competitive and cell-permeable CAS# 1062169-56-5

WYE-354

Catalog No. BCC1059----Order now to get a substantial discount!

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Chemical structure

WYE-354

3D structure

Chemical Properties of WYE-354

Cas No. 1062169-56-5 SDF Download SDF
PubChem ID 44219749 Appearance Powder
Formula C24H29N7O5 M.Wt 495.53
Type of Compound N/A Storage Desiccate at -20°C
Synonyms WYE 354;WYE354
Solubility DMSO : 6.67 mg/mL (13.46 mM; Need ultrasonic)
Chemical Name methyl 4-[6-[4-(methoxycarbonylamino)phenyl]-4-morpholin-4-ylpyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate
SMILES COC(=O)NC1=CC=C(C=C1)C2=NC3=C(C=NN3C4CCN(CC4)C(=O)OC)C(=N2)N5CCOCC5
Standard InChIKey IMXHGCRIEAKIBU-UHFFFAOYSA-N
Standard InChI InChI=1S/C24H29N7O5/c1-34-23(32)26-17-5-3-16(4-6-17)20-27-21(29-11-13-36-14-12-29)19-15-25-31(22(19)28-20)18-7-9-30(10-8-18)24(33)35-2/h3-6,15,18H,7-14H2,1-2H3,(H,26,32)
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-354

DescriptionWYE-354 is a potent cell-permeable inhibitor of mTOR with IC50 value of 4.3 nM.
TargetsmTOR    
IC504.3 nM     

Protocol

Cell experiment [1]:

Cell lines

HEK293 cells

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

1 h; 5 μM

Applications

To test directly the inhibition of mTORC2 catalytic activity in vitro, we immunoprecipitated mTORC2 and mTORC1 from HEK293 cells and performed immune-complex kinase assay of the mTORC2-specific substrate His6-AKT or the mTORC1 substrate His6-S6K. AKT (S473) phosphorylation was dose dependently inhibited by WYE-354.

Animal experiment [1]:

Animal models

BALB/c nu/nu female mice

Dosage form

50 mg/kg; intraperitoneal injection

Application

Nude mice bearing the PTEN-null PC3MM2 tumors were administered i.p. with vehicle or 50 mg/kg WYE-354.Tumor lysates prepared at 1, 2, 4, and 6 hours after dosing were immunoblotted for levels of P-S6K(T389), P-AKT(S473), and P-AKT(T308). Quantification of the immunoblotting results indicated that WYE-354 completely inhibited P-S6K (T389) for at least 6 hours and substantially inhibited P-AKT(S473) for 6 hour. As expected, P-AKT(T308) in the same tumors was variably but not significantly inhibited. WYE-354 selectively inhibited P-AKT(S473) via targeting mTORC2.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Yu K, Toral-Barza L, Shi C, et al. Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin[J]. Cancer research, 2009, 69(15): 6232-6240.

WYE-354 Dilution Calculator

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Preparing Stock Solutions of WYE-354

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.018 mL 10.0902 mL 20.1804 mL 40.3608 mL 50.451 mL
5 mM 0.4036 mL 2.018 mL 4.0361 mL 8.0722 mL 10.0902 mL
10 mM 0.2018 mL 1.009 mL 2.018 mL 4.0361 mL 5.0451 mL
50 mM 0.0404 mL 0.2018 mL 0.4036 mL 0.8072 mL 1.009 mL
100 mM 0.0202 mL 0.1009 mL 0.2018 mL 0.4036 mL 0.5045 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-354

WYE-354 is a powerful and selective ATP-competitive kinase heterocyclic inhibitors with biochemical IC50 of 5 nM against mTOR.[1]

WYE-354 displays very specific selectivity to PI3K families (>100-fold to PI3K and >500-fold to PI3K), but it can’t inhibit some protein kinases. May cancer cell lines including MDA-MB-468 and U87MG can be inhibited by WYE-354 in 0.3–1 mM range.[1]

In-vitro study has proved that WYE-354 can inhibit substrate phosphorylation such as p-4E-BP1 T37/46 and p-Akt S473 by mTORC1 and mTORC2. WYE-354 can reduce Akt downstream function and block the propagation of the cancer cell lines with an IC50 value from sub-micromolar to micromolar range [3]. These effects were consistent with the G1 cell cycle arrest in two cell lines, including rapamycin-sensitive and rapamycin-resistant cells. It is believed to induce apoptosis, repress the global protein synthesis, and down-regulate many angiogenic factors.[3]

References:
[1] Qingsong Liu, Carson Thoreen, Jinhua Wang, David Sabatini, Nathanael S. Gray. mTOR mediated anti-cancer drug discovery. Drug Discovery Today. 2009. 6(2): 47-55.
[2] Shi-Yong Sun. mTOR kinase inhibitors as potential cancer therapeutic drugs. Cancer Letters. 28 October 2013. 340(1): 1-8.

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References on WYE-354

Rapamycin and WYE-354 suppress human gallbladder cancer xenografts in mice.[Pubmed:26397134]

Oncotarget. 2015 Oct 13;6(31):31877-88.

Gallbladder cancer (GBC) is a highly malignant tumor characterized by a poor response to chemotherapy and radiotherapy. We evaluated the in vitro and in vivo antitumor efficacy of mTOR inhibitors, rapamycin and WYE-354. In vitro assays showed WYE-354 significantly reduced cell viability, migration and invasion and phospho-P70S6K expression in GBC cells. Mice harboring subcutaneous gallbladder tumors, treated with WYE-354 or rapamycin, exhibited a significant reduction in tumor mass. A short-term treatment with a higher dose of WYE-354 decreased the tumor size by 68.6% and 52.4%, in mice harboring G-415 or TGBC-2TKB tumors, respectively, compared to the control group. By contrast, treatment with a prolonged-low-dose regime of rapamycin almost abrogated tumor growth, exhibiting 92.7% and 97.1% reduction in tumor size, respectively, compared to control mice. These results were accompanied by a greater decrease in the phosphorylation status of P70S6K and a lower cell proliferation Ki67 index, compared to WYE-354 treated mice, suggesting a more effective mTOR pathway inhibition. These findings provide a proof of concept for the use of rapamycin or WYE-354 as potentially good candidates to be studied in clinical trials in GBC patients.

Autophagy inhibition sensitizes WYE-354-induced anti-colon cancer activity in vitro and in vivo.[Pubmed:27020593]

Tumour Biol. 2016 Sep;37(9):11743-11752.

Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTORC2 are frequently dysregulated in human colon cancers. In the present study, we evaluated the potential anti-colon cancer cell activity by a novel mTORC1/2 dual inhibitor WYE-354. We showed that WYE-354 was anti-survival and anti-proliferative when adding to primary (patient-derived) and established (HCT-116, HT-29, Caco-2, LoVo, and DLD-1 lines) colon cancer cells. In addition, WYE-354 treatment activated caspase-dependent apoptosis in the colon cancer cells. Mechanistically, WYE-354 blocked mTORC1 and mTORC2 activation. Meanwhile, it also induced autophagy activation in the colon cancer cells. Autophagy inhibitors (bafilomycin A1 and 3-methyladenine), or shRNA-mediated knockdown of autophagy elements (Beclin-1 and ATG-5), remarkably sensitized WYE-354-mediated anti-colon cancer cell activity in vitro. Further studies showed that WYE-354 administration inhibited HT-29 xenograft growth in severe combined immunodeficient (SCID) mice. Importantly, its activity in vivo was further potentiated with co-administration of the autophagy inhibitor 3-MA. Phosphorylations of Akt (Ser-473) and S6 were also decreased in WYE-354-treated HT-29 xenografts. Together, these pre-clinical results demonstrate the potent anti-colon cancer cell activity by WYE-354, and its activity may be further augmented with autophagy inhibition.

Description

WYE-354 is an ATP-competitive mTOR inhibitor with an IC50 of 5 nM. WYE-354 also inhibits PI3Kα and PI3Kγ with IC50s of 1.89 μM and 7.37 μM, respectively. WYE-354 inhibits both mTORC1 and mTORC2.

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