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    AZD8186
    AZD8186

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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 #: V0152
    CAS #: 1627494-13-6Purity ≥98%

    Description: AZD8186 (also known as AZD) is a novel, potent  and selective inhibitor of PI3Kβ (phosphatidylinositol 3-kinase β) with potential anticancer activity. It inhibits PI3Kβ and PI3Kδ with IC50 of 4 nM and 12 nM, respectively, and showed high selectivity for PI3Kβ and PI3Kδ over PI3Kγ (IC50=675 nM). AZD8186 exhibits significant anti-tumour activity in PTEN-deficient preclinical models, particularly when combined with anti-androgens or the dual mTORC1/2 inhibitor vistusertib (AZD2014). AZD8186 has a potential for treatment of PTEN-deficient tumors.

    References:J Med Chem. 2015 Jan 22;58(2):943-62.

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    Molecular Weight (MW)

    457.47

    Formula

    C24H25F2N3O4

    CAS No.

    1627494-13-6

    Storage

    -20℃ for 3 years in powder form

    -80℃ for 2 years in solvent

    Solubility (In vitro)

    DMSO: 91 mg/mL warming (198.9 mM)

    Water:<1 mg/mL

    Ethanol: 35 mg/mL warming (76.5 mM)

    Solubility (In vivo)

    10% DMSO + 60% TEG+ 30% WFI: 16mg/mL 

    Synonym/Chemical Name

    AZD8186; AZD 8186; AZD-8186; (R)-8-(1-((3,5-difluorophenyl)amino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide


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    In Vitro

    Kinase Assay: The inhibition of PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ human recombinant PI3K isoforms is evaluated using a Kinase-Glo Plus Assay Kit. 12 point half-log concentration-response curves with a top concentration of 100 μM are constructed by dispensing DMSO solubilised compounds into white 384-well medium-binding microplates using an Echo 555. 3 μL of the appropriate PI3K in Tris buffer (50 mM Tris pH7.4, 0.05% CHAPS, 2.1 mM DTT, and 10 mM MgCl2) is added. The plate is covered and allowed to pre-incubate with compound for 20 minutes prior to addition of 3 μL of substrate solution containing PIP2 and ATP. The enzyme reaction is stopped after 80 minutes by the addition of Kinase Glo detection solution. Plates are covered and incubated for 30 minutes at room temperature before the luminescence signal is read using a PHERAstar plate reader. The final concentrations of DMSO, ATP and PIP2 in the assay are 2%, 8 μM, and 80 μM respectively. The final concentrations of PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ are respectively 20 nM, 20 nM, 45 nM and 30 nM. For PI3Kα, PI3Kβ and PI3Kδ the concentration of active enzyme is determined as outlined in the enzyme assay tight binding limit determination section. For PI3Kγ the concentration of enzyme is determined by Bradford assay. IC50 values are calculated using Genedata Screener. 


    Cell Assay: Cells (A subset of cancer cell lines) are seeded in 96-well plates, at a density to allow for logarithmic growth during the 72 hour assay, and incubated overnight at 37°C, 5% CO2. Cells are treated with AZD8186 (30 to 0.003 μM) for 72 hours and cell proliferation measured by MTS. The CellTiter Aqueous Non-Radioactive Cell Proliferation Assay reagent is used in accordance with the manufacturer’s protocol and Absorbance measured with Tecan Ultra instrument. Pre-dose measurements are made and the concentration needed to reduce the growth of treated cells to half that of untreated cells (GI50) values are determined.

    AZD8186 potently inhibits p-Akt in MDA-MB-468 cells sensitive to PI3Kβ inhibition and Jeko B cells sensitive to PI3Kδ inhibition with IC50 of 3 nM and 4 nM, respectively. AZD8186 shows preferred growth inhibition activity in most PTEN deficient cell lines with GI50 of<1 μM.

    In VivoIn nude mice bearing PTEN-deficient PC3 prostate tumor xenografts, AZD8186 (100 mg/kg, p.o.) strongly inhibits Akt phosphorylation levels, and causes significant tumor growth inhibition. When used in combination with ABT, AZD8186 (60 mg/kg, p.o.) results in complete inhibition of tumor growth. In the mouse PTEN-null TNBC models HCC70 and MDA-MB-468, and the prostate models HID28, AZD8186 (50 mg/kg, p.o.) also inhibits the growth of tumors. Combination therapy using AZD8186 with androgen deprivation results in long-lasting tumor regression, which persisted after treatment cessation.
    Animal modelNude mice bearing PTEN-deficient PC3 prostate tumor xenografts
    Formulation & DosageDissolved in  10% DMSO / 60% TEG/ 30% WFI; 100 mg/kg; oral administration
    References

    [1] Barlaam B, et al. J Med Chem. 2015, 58(2), 943-962.


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

    AZD8186

    Activity of AZD8186. Mol Cancer Ther. 2015, 14(1), 48-58.

    AZD8186

    In vivo activity of AZD8186

    AZD8186

    AZD8186 combines with docetaxel.


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