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    WYE-687
    WYE-687

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0201
    CAS #: 1062161-90-3Purity ≥98%

    Description: WYE-687 is a novel, potent, ATP-competitive and selective inhibitor of mTOR (mammalian target of rapamycin) with potential antitumor activity. It inhibits mTOR with IC50 of 7 nM; WYE687showed potent antiproliferative activity in vitro and high antitumor efficacy in vivo.

    References: Cancer Res. 2009 Aug 1;69(15):6232-40

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    Molecular Weight (MW)528.61
    FormulaC28H32N8O3
    CAS No.1062161-90-3
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 0.5 mg/mL (0.94 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Other info

    Chemical Name: methyl (4-(4-morpholino-1-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)carbamate

    InChi Key: VDOCQQKGPJENHJ-UHFFFAOYSA-N

    InChi Code: InChI=1S/C28H32N8O3/c1-38-28(37)31-22-6-4-21(5-7-22)25-32-26(35-13-15-39-16-14-35)24-18-30-36(27(24)33-25)23-8-11-34(12-9-23)19-20-3-2-10-29-17-20/h2-7,10,17-18,23H,8-9,11-16,19H2,1H3,(H,31,37)

    SMILES Code: O=C(OC)NC1=CC=C(C2=NC(N3CCOCC3)=C4C(N(C5CCN(CC6=CC=CN=C6)CC5)N=C4)=N2)C=C1

    SynonymsWYE687; WYE-687; WYE 687


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    In Vitro

    Kinase Assay: DELFIA Format of Purified FLAG-TOR: The routine assays with purified FLAG-TOR (FL and 3.5) are performed in 96-well plates as follows. Enzymes are first diluted in kinase assay buffer (10 mM Hepes (pH 7.4), 50 mM NaCl, 50 mM β-glycerophosphate, 10 mM MnCl2, 0.5 mM DTT, 0.25 lM microcystin LR, and 100 lg/mL BSA). To each well, 12 μL of the diluted enzyme is mixed briefly with 0.5 μL test inhibitor or control vehicle dimethyl sulfoxide (DMSO). The kinase reaction is initiated by adding 12.5 μL kinase assay buffer containing ATP and His6-S6K to give a final reaction volume of 25 μL containing 800 ng/mL FLAG-TOR, 100 μM ATP, and 1.25 μM His6-S6K. The reaction plate is incubated for 2 hours (linear at 1-6 hour) at room temperature with gentle shaking and then terminated by adding 25 μL Stop buffer (20 mM Hepes (pH 7.4), 20 mM EDTA, and 20 mM EGTA). The DELFIA detection of the phosphorylated (Thr-389) His6-S6K is performed at room temperature using a monoclonal anti-P(T389)- p70S6K antibody (1A5) labeled with Europium-N1- ITC (Eu) (10.4 Eu per antibody). Fortyfive microliters of the terminated kinase reaction mixture are transferred to a MaxiSorp plate containing 55 μL PBS. The His6-S6K is allowed to attach for 2 hour after which the wells are aspirated and washed once with PBS. One hundred microliters of DELFIA buffer with 40 ng/mL Eu-P(T389)-S6K antibody is added. The antibody binding is continued for 1 hour with gentle agitation. The wells are then aspirated and washed four times with PBS containing 0.05% Tween 20 (PBST). One hundred microliters of DELFIA Enhancement solution is added to each well and the plates are read in a PerkinElmer Victor model plate reader. Data obtained are used to calculate enzymatic activity and enzyme inhibition by potential inhibitors. 


    Cell Assay: For cell cycle analysis, cells (MDA361, U87MG, HCT116, LNCap and HT29 cells) are seeded in 96-well culture plates at 10,000 cells per well for 24 hours, treated with various inhibitors for 24 hours or 48 hours. Following treatment, cells are harvested, washed with PBS and fixed overnight at -20 °C in 70% ethanol. Cells are washed, stained with propidium iodide and analyzed for cell cycle profile (acquired 5000 cells/well) on Guava PCA-96 instrument according to the Guava Cell Cycle Protocol.

    Immune-complex kinase assay shows mTORC2-specific substrate His6-AKT or the mTORC1 substrate His6-S6K is dose dependently inhibited by WYE-687. WYE-687 globally inhibits mTOR signaling and AKT function in cellular models dose dependently. WYE-678 profoundly inhibits cap-dependent and global protein synthesis in MDA361, human breast cancer cells. WYE-687 shows antiproliferative effects in various cancer cell lines involving G1 cell cycle arrest and selective apoptosis. WYE-687 down-regulate angiogenic factors, VEGF and HIF-1α, in U87MG, MDA361 and LNCap cells.

    In VivoU937 cells are inoculated into the flanks of SCID/beige mice. When xenografted tumors reach a volume around 100 mm3, mice are orally administrated with either vehicle control (5% ethanol, 2% Tween 80, and 5% polyethylene glycol-400) or WYE-687 (5 or 25 mg/kg) daily for a total of 7 days. The WYE-687 regimen utilized in this study is based on preexperimental results and related studies. WYE-687 administration (5 or 25 mg/kg, daily) significantly inhibits U937 xenograft tumor growth in SCID mice, and the in vivo activity by WYE-687 is dose-dependent. At day 15, the 5 mg/kg WYE-687-treated tumors and 25 mg/kg WYE-687-treated tumors are 50% and 75% smaller than the vehicle control tumors, respectively. Tumor weights of WYE-687-treated mice are also significantly lower than that of vehicle group. Oral administration of WYE-687 potently inhibits U937 leukemic xenograft tumor growth in SCID mice, without causing significant toxicities
    Animal modelMice: U937 cells (2×106 cells/mice, suspended in 100 mL of culture medium) are injected into the right flanks of 6-week-old male CB17 severe combined immunodeficient (SCID)/beige mice, and cells are allowed to grow to palpable tumors. When tumors reach a volume around 100 mm3, animals are randomly assigned to three groups: WYE-687 (5 mg/kg body weight), WYE- 687 (25 mg/kg body weight) or the vehicle control (5% ethanol, 2% Tween 80, and 5% polyethylene glycol-400). WYE-687 and vehicle control are freshly prepared, and given by oral gavage daily for 7 consecutive days. Tumor sizes are measured. At the end of experiment, the animals are killed, and the tumors are removed and weighted.
    Formulation & Dosage5, 25 mg/kg; dissolved in 5% ethanol, 2% Tween 80, and 5% polyethylene glycol-400; oral
    References

    Cancer Res. 2009 Aug 1;69(15):6232-40; Cheng F, et al. Preclinical evaluation of WYE-687, a mTOR kinase inhibitor, as a potential anti-acute myeloid leukemia agent. Biochem Biophys Res Commun. 2016 Feb 5;470(2):324-330.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    WYE-687

    Novel pyrazolopyrimidines are ATP-competitive inhibitors of mTOR. Cancer Res. 2009 Aug 1;69(15):6232-40

    WYE-687

    mTOR kinase inhibitors profoundly inhibit cap-dependent and global protein synthesis in cancer cells.



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