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    CP-466722
    CP-466722

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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 #: V2528
    CAS #: 1080622-86-1Purity ≥98%

    Description: CP-466722 is a novel, specific and reversible ATM inhibitor with an IC50 value of 4.1 μM, it does not affect ATR and inhibits PI3K or PIKK family members in cells. Inhibition of cellular ATM kinase activity was rapidly and completely reversed by removing CP466722. CP-466722 is regarded as a promising drug to increase tumor cells sensitivity to IR. When tested with Hela, MCF-7 and mouse cells pre-treated with IR which induced the increase in ATM-dependent phosphorylation events and then CP-466722 treatment resulted in the disruption of ATM-dependent phosphorylation events and inhibiton of ATM-dependent p53 inducetion at the minimal dose of 6 μM. 

    References: Cancer Res. 2008 Sep 15;68(18):7466-74; J Biomol Screen. 2014 Apr;19(4):538-46.

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    Molecular Weight (MW)349.35
    FormulaC17H15N7O2
    CAS No.1080622-86-1
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 0.28 mg/mL (0.8 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)Chemical Name: 1-(6,7-dimethoxyquinazolin-4-yl)-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-amine
    InChi Key: ILBRKJBKDGCSCB-UHFFFAOYSA-N
    InChi Code: InChI=1S/C17H15N7O2/c1-25-13-7-10-12(8-14(13)26-2)20-9-21-16(10)24-17(18)22-15(23-24)11-5-3-4-6-19-11/h3-9H,1-2H3,(H2,18,22,23)
    SMILES Code: COC1=C(C=C2C(=C1)C(=NC=N2)N3C(=NC(=N3)C4=CC=CC=N4)N)OC
    SynonymsCP-466722; CP 466722; CP466722


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    In Vitro

    In vitro activity: In vitro, CP-466722 is identified as a potential inhibitor to decrease the activity of purified ATM kinase to phosphorylate GST-p53(1–101) substrate. In addition, CP-466722 also shows the inhibitory activities against abl and src kinases. In HeLa cells, CP-466722 at doses of 6μM, results in the inhibition in ATM-dependent phosphorylation by reversibly inhibiting ionizing radiation (IR)-induced ATM kinase activity. Besides, ATM-dependent p53 induction is also inhibited by CP-466722 in MCF-7 human breast cancer cells and primary and immortalized diploid human fibroblasts. In response to IR, CP-466722 increased proportion of cells with G2/M DNA content and reduces proportion of cells with G1-phase DNA content in HeLa cells. Transient exposure to CP-466722 for a period of 4 hours sensitizes HeLa cells to IR without affecting cell plating nor cell viability.


    Kinase Assay: To screen for small molecule inhibitors of ATM kinase activity, an in vitro kinase assay is adapted, and an ELISA assay develops which measured the phosphorylation status of the ATM downstream target p53. Recombinant GST-p53(1-101) and full-length Flag-tagged ATM & ATR are purified for use in the ELISA and in vitro kinase assays. Briefly, Nunc 96 well Maxisorp plates are coated overnight (4 °C) with 2μg of purified, recombinant GST-p53(1-101) in PBS. All subsequent incubations are performed at room temperature. The plates are washed (0.05%v/v-Tween/PBS) before addition of purified recombinant full-length ATM kinase (30 ng–60 ng) in a final volume of 80μL of reaction buffer (20 mM HEPES, 50 mM NaCl, 10 mM MgCl2, 10 mM MnCl2, 1 mM DTT and 1 μM ATP) in the presence or absence of CP-466722. CP-466722 (10μM) is added to plates in duplicate and the kinase assay is incubated (90 minutes). Plates are washed (0.05%v/v-Tween/PBS), blocked (1hour, 1%w/v-BSA/PBS) and rinsed before anti-Phospho(Ser15)-p53 antibody (1:1000/PBS) is added to the plates and incubated (1hour). To reduce non-specific binding plates are washed (0.05%v/v-Tween/PBS) prior to incubation (1hour) with HRP-conjugated goat anti-rabbit IgG secondary antibody (1:5000/PBS). Secondary antibody that is linked to the phosphorylated GST-p53(1–101) protein is detected with TMB substrate reagent. Plates are developed (15 minutes–30 minutes) and the reaction is stopped (1 M H2SO4 final concentration) before absorbance is determined (λ450nm). CP-466722 that inhibits ATM kinase activity in ELISA assays, are characterized with respect to inhibition of ATM/ATR kinases using in vitro kinase assays. Western blotting using the anti-Phospho(Ser15)-p53 antibody is used as a readout of ATM/ATR inhibition. Extended analysis of CP466722 (10 μM) against a commercially available panel of kinases is performed by Upstate.


    Cell Assay: HeLa or A-T (GM02052 expressing hTERT) cells are plated in triplicate and incubated for 24 hours. Cells are pre-treated: DMSO, CP466722 or KU55933 prior to IR (0-10Gy). Cells are incubated for 4 hours following IR before media is removed, cells washed (PBS), trypsined, counted and re-plated (2000 cells/plate, 10 cm plates) in the absence of drug and incubated for 10 days. Prior to colony counting, cells are washed (PBS), stained (PBS, 0.0037%v/v-formaldehyde, 0.1%w/v-crystal violet), rinsed (dH2O) and dried. Defined populations (>50 cells) are counted as one surviving colony, data are calculated as percentage surviving colonies relative to control plates +/− SE.

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    References

    Cancer Res. 2008 Sep 15;68(18):7466-74; J Biomol Screen. 2014 Apr;19(4):538-46.


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

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