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    ZSTK474
    ZSTK474

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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 #: V0113
    CAS #: 475110-96-4Purity ≥98%

    Description: ZSTK474 is a novel, potent and ATP-competitive pan-PI3K inhibitor (class I) with potential anticancer activity. It strongly inhibits the growth of tumor cells by directly inhibiting the activity of all class I PI3K isoforms including PI3Kα, PI3-Kβ, PI3-Kγ, PI3-Kδ with IC50 values of 16 nM, 44 nM, 49 nM, and 4.6 nM, respectively. ZSTK474 has high selectivity over other classes of PI3K and protein kinases. ZSTK474 also inhibited the bone-resorbing activity of mature osteoclasts. Studies showed that 0.1μM of ZSTK474 completely prevented pit formation by osteoclasts.

    References:Biochim Biophys Acta. 2008 Jan;1784(1):159-85.

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    Molecular Weight (MW)

    417.41

    Formula

    C19H21F2N7O2 

    CAS No.

    19545-26-7

    Storage

    -20℃ for 3 years in powder form

    -80℃ for 2 years in solvent

    Solubility (In vitro)

    DMSO: 21 mg/mL (50.31 mM)

    Water:<1 mg/mL (slightly soluble or insoluble)

    Ethanol: <1 mg/mL

    Solubility (In vivo)

    0.5% hydroxyethyl cellulose: 30mg/mL

    Chemical Name/Synonyms

    ZSTK474; ZSTK-474; ZSTK 474; 4-[4-[2-(difluoromethyl)benzimidazol-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl]morpholine


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    In Vitro

    Kinase Assay:  A549 cells are lysed in a buffer containing 20 mM Tris-HCl (pH 7.5), 150 mM NaCl, 5 mM EDTA, and 1% Igepal CA-630, the lysates are centrifuged at 20,000 g and 4 °C for 10 minutes, and the supernatants are used as cell lysate (protein = 2-4 mg/mL). To immunoprecipitate PI3K, 200 μL of cell lysate are incubated with anti-p85 polyclonal antibody and protein G-agarose (5 μL). PI3Kα, PI3Kβ, and PI3Kδ can be immunoprecipitated by the anti-p85 polyclonal antibody. Agarose beads containing immunoprecipitates are washed twice with buffer A (20 mM Tris-HCl at pH 7.5, 150 mM NaCl, 5 mM EDTA, and 1% Igepal CA-630), once with buffer B (500 mM LiCl and 100 mM Tris-HCl at pH 7.5), once with distilled water, and once with buffer C (100 mM NaCl and 20 mM Tris-HCl at pH 7.5). Immunoprecipitates are suspended in 20 μL of buffer C containing phosphatidylinositol of 200 μg/mL. The mixture is preincubated with increasing concentrations of ZSTK474 at 25 °C for 5 minutes. [γ-32P]ATP (2 μCi per assay mixture; final concentration, 20 μM) and MgCl2(final concentration, 20 mM) are added to start the reaction. The reaction mixture is incubated at 25 °C for 20 minutes. Phosphorylated products of phosphatidylinositol are separated by thin-layer chromatography and visualized by autoradiography. The phosphatidylinositol-3-phosphate region is scraped from the plate, and radioactivity is also measured with liquid scintillation spectroscopy. The level of inhibition for ZSTK474 is determined as the percentage of 32P counts per minute obtained without ZSTK474.

     

    Cell Assay: Cells (MCF-7, HT-29, HCT-116, OVCAR3, A549, et al.) are exposed to increasing concentrations of ZSTK474 for 48 hours. The inhibition of cell proliferation is assessed by measuring changes in total cellular protein by use of a sulforhodamine B assay. Apoptosis is assessed by chromatin condensation or by flow cytometry. For chromatin condensation assay, cells are stained with Hoechst 33342 and examined by fluorescence microscopy. Morphologic changes induced by ZSTK474, such as the condensation of chromatin, are indicative of apoptosis. For flow cytometry analysis, cells are harvested, washed with ice-cold PBS, and fixed in 70% ethanol. Cells are then washed twice with ice-cold PBS again, treated with RNase A (500 μg/mL) at 37 °C for 1 hour, and stained with propidium iodide (25 μg/mL). The DNA content of the cells is analyzed with a flow cytometer.

    ZSTK474 at 1 μM potently reduces PI3K activity to 4.7% of the control level, whereas LY2194002 only reduces the activity to 44.6% of the control. ZSTK474 inhibits the activities of recombinant p110β, -γ, and -δ with IC50 of 17 nM, 53 nM, and 6 nM, respectively. ZSTK474 shows potent antiproliferative activity against a panel of 39 human cancer cell lines with mean GI50 of 0.32 μM, more effectively than that of LY294002 or wortmannin with mean GI50 of 7.4 μM or 10 μM, respectively. ZSTK474 treatment at 1 μM blocks membrane ruffling and generation of PIP3 induced by platelet-derived growth factor in murine embryonic fibroblasts (MEFs). ZSTK474 at 10 μM induces apoptosis in OVCAR3 cells, and induces complete G1-phase arrest but not apoptosis in A549 cells. ZSTK474 treatment at 0.5 μM significantly decreases the level of phosphorylated Akt and GSK-3β, as well as the cyclin D1 protein expression. ZSTK474 also inhibits the phosphorylation of other downstream signaling components that are involved in regulating cell proliferation including FKHRL1, FKHR, TSC-2, mTOR, and p70S6K in a dose-dependent manner. ZSTK474 does not inhibit mTOR at 0.1 μM, and even at a concentration of 100 μM, ZSTK474 inhibits mTOR activity less than 40%.

    In Vivo

    Oral administration of ZSTK474 inhibits the growth of subcutaneously implanted mouse B16F10 melanoma tumors in a dose-dependent manner, producing tumor regression of 28.5%, 7.1%, or 4.9% on day 14 at 100, 200, or 400 mg/kg, respectively, which is superior to that of the four major anticancer drugs irinotecan, cisplatin, doxorubicin, and 5-fluorouracil at their respective maximum tolerable doses with tumor regression of 96%, 35.7%, 24%, or 68.3%, respectively. ZSTK474 treatment at 400 mg/kg completely inhibits the growth of A549, PC-3, and WiDr xenografts in mice, and induces the regression of A549 xenograft tumors. ZSTK474 significantly inhibits tumor growth in the RXF-631L xenograft model, correlated with a significantly reduced number of microvessels in the ZSTK474-treated mice. Oral administration of ZSTK474 ameliorates the progression of adjuvant-induced arthritis (AIA) in rats.

    Animal model

    Male BDF1 mice injected subcutaneously with B16F10 cells, and female BALB/c nude mice inoculated subcutaneously with A549, PC-3, or WiDr cells

    Formulation & Dosage

    Suspended in 5% hydroxypropylcellulose in water as a solid dispersion form; mg400/kg; oral

    References

    [1] Yaguchi S, et al. J Natl Cancer Inst, 2006, 98(8), 545-556.


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

    ZSTK474

    ZSTK474 alleviates neurological deficits and reduces infarct volume in a model of ischemic reperfusion. J Neuroinflammation. 2016; 13(1): 192.

    ZSTK474

    ZSTK474 inhibits the expression of Iba-1 and GFAP at 72 h after cerebral reperfusion injury. J Neuroinflammation. 2016; 13(1): 192.

    ZSTK474

    Double immunofluorescent staining for the microglial/macrophage marker Iba-1 and detrimental or restorative state markers.  J Neuroinflammation. 2016; 13(1): 192.

    ZSTK474

    ZSTK474 inhibits pro-inflammatory cytokines and promotes anti-inflammatory cytokines. J Neuroinflammation. 2016; 13(1): 192.

    ZSTK474

    ZSTK474 reduces P-AKT and P-p70S6k protein levels. ZSTK474 suppresses phosphorylation of AKT and other downstream compounds. J Neuroinflammation. 2016; 13(1): 192.

    ZSTK474

    Summary diagram illustrates a hypothesis for how ZSTK474 exerts its effects on ischemic reperfusion injury. J Neuroinflammation. 2016; 13(1): 192.


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