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    PF-04691502
    PF-04691502

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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 #: V0123
    CAS #: 1013101-36-4Purity ≥98%

    Description: PF-04691502 is a novel, potent, ATP-competitive and dual inhibitor of PI3K (phosphatidylinositol 3 kinase) and mTOR (mammalian target of rapamycin) with Ki of 1.8 nM/2.1 nM/1.6 nM/1.9 nM and 16 nM in cell-free assays. It shows little activity against either Vps34, AKT, PDK1, p70S6K, MEK, ERK, p38, or JNK. PF-04691502 is a potential anticancer drug that acts by inhibiting class I PI3K and mTOR in the PI3K/AKT/mTOR signaling pathway as measured by fluorescence polarization kinase assay, cell, mice and other animal trials. Treatment with PF-04691502  results in the suppression of tumor growth in cancer cells overexpressing PI3K/mTOR.

    References:  Mol Cancer Ther. 2011 Nov;10(11):2189-99; Mol Cancer Ther. 2011 Aug;10(8):1440-9. 


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    Molecular Weight (MW)425.48
    FormulaC22H27N5O4
    CAS No.1013101-36-4
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 14 mg/mL (32.9 mM)
    Water:<1 mg/mL
    Ethanol: <1 mg/mL
    Synonym PF-04691502; PF 04691502; PF04691502; PF 4691502; PF4691502; PF-4691502
    Chemical Name2-amino-8-[4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7-one


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    In Vitro

    Kinase Assay: The fluorescence polarization assay for ATP competitive inhibition is done as follows: mPI3Kα dilution solution (90 nM) is prepared in fresh assay buffer (50 mM Hepes pH 7.4, 150 mM NaCl, 5 mM DTT, 0.05% CHAPS) and kept on ice. The enzyme reaction contains 0.5 nM mouse PI3Kα (p110α/p85α complex purified from insect cells), 30 μM PIP2, PF-04691502 (0, 1, 4, and 8 nM), 5 mM MgCl2, and 2-fold serial dilutions of ATP (0–800 μM). Final dimethyl sulfoxide is 2.5%. The reaction is initiated by the addition of ATP and terminated after 30 minutes with 10 mM EDTA. In a detection plate, 15 uL of detector/probe mixture containing 480 nM GST-Grp1PH domain and 12 nM TAMRA tagged fluorescent PIP3 in assay buffer is mixed with 15 uL of kinase reaction mixture. The plate is shaken for 3 minutes, and incubated for 35 to 40 minutes before reading on an LJL Analyst HT.

     

    Cell Assay: BT20, U87MG, and SKOV3 cells are plated at 3,000 cell/well in 96-well culture plates in growth medium with 10% FBS. Cells are incubated overnight and treated with DMSO (0.1% final) or serial diluted compound for 3 days. Resazurin is added to 0.1 mg/mL. Plates are incubated at 37 °C in 5% CO2 for 3 hours. Fluorescence signals are read as emission at 590 nm after excitation at 530 nm. IC50 values are calculated by plotting fluorescence intensity to drug concentration in nonlinear curve.

    PF-04691502 potently inhibits recombinant class I PI3K and mTOR in biochemical assays and suppresses transformation of avian fibroblasts mediated by wild-type PI3K γ, δ, or mutant PI3Kα. In PIK3CA-mutant and PTEN-deleted cancer cell lines, PF-04691502 reduces phosphorylation of AKT T308 and AKT S473 (IC(50) of 7.5-47 nM and 3.8-20 nM, respectively) and inhibits cell proliferation (IC(50) of 179-313 nM). PF-04691502 inhibits mTORC1 activity in cells as measured by PI3K-independent nutrient stimulated assay, with an IC(50) of 32 nM and inhibits the activation of PI3K and mTOR downstream effectors including AKT, FKHRL1, PRAS40, p70S6K, 4EBP1, and S6RP. Short-term exposure to PF-04691502 predominantly inhibits PI3K, whereas mTOR inhibition persists for 24 to 48 hours. PF-04691502 induces cell cycle G(1) arrest, concomitant with upregulation of p27 Kip1 and reduction of Rb.

    In Vivo

    Antitumor activity of PF-04691502 is observed in U87 (PTEN null), SKOV3 (PIK3CA mutation), and gefitinib- and erlotinib-resistant non-small cell lung carcinoma xenografts. PF-04691502 inhibits tumor growth at 7 days by 72%. FDG-PET imaging revealed that PF-04691502 reduces glucose metabolism dramatically. Tissue biomarkers of PI3K/mTOR pathway activity, p-AKT (S473), and p-RPS6 (S240/244), are also dramatically inhibited following PF-04691502 treatment.

    Animal model

    LSL-KrasG12D heterozygous mice (B6.129-Kras tm4Tyj) and Ptendel mice (c;129S4-Pten tm1Hwu/J), Orthotopic transplant of ovarian tumors

    Formulation & Dosage

    Dissolved in 0.5% methylcellulose; 10 mg/kg; oral

    References

    [1] Yuan J, Mol Cancer Ther, 2011, 10(11), 2189-2199[2] Kinross KM, Mol Cancer Ther, 2011, 10(8), 1440-1449.

     


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

    PF-04691502

    Kinross KM, Mol Cancer Ther, 2011, 10(8), 1440-1449

    PF-04691502
    PF-04691502


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