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    MK-2206 2HCl
    MK-2206 2HCl

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    产品仅用于科学研究,不针对患者销售
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    InvivoChem目录号 #: V0155
    CAS号码 #: 1032350-13-2 纯度 ≥98%

    Description: MK-2206 dihydrochloride (2HCl) is a novel, potent, orally bioavailable and highly selective allosteric inhibitor of the serine/threonine protein kinase Akt1/2/3 with potential anticancer activity. It inhibits Akt1/2/3 with IC50 of 8 nM/12 nM/65 nM in cell-free assays, respectively; it has no/little inhibitory activities against 250 other protein kinases observed. MK-2206 has potential anticancer activity by inhibiting the phosphorylation of Thr308 and Ser 473 of Akt. MK-2206 suppresses Akt signalling pathway and promoting cancer cell death as a single agent as well as in combination with other chemotherapeutic agents. MK-2206 enhance the sensitivity to through apoptosis and enhance the sensitivity to rapamycin via reactive oxygen species. 

    References: Mol Cancer Ther. 2010 Jul;9(7):1956-67; Cancer Res. 2011 Apr 1;71(7):2654-63.

    Related CAS: 1032349-77-1 (HCl); 1032350-13-2 (2HCl); 1032349-93-1 (free base);

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    Molecular Weight (MW)

    480.39

    Formula

    C25H21N5O.2HCl

    CAS No.

    1032350-13-2 (2HCl); 

    Storage

    -20℃ for 3 years in powder form

    -80℃ for 2 years in solvent

    Solubility (In vitro)

    DMSO: 14 mg/mL (29.1 mM)

    Water:<1 mg/mL

    Ethanol: <1 mg/mL

    Solubility (In vivo)

    15% Captisol: 17 mg/mL

    Chemical Name/Synonym

    8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one;dihydrochloride; MK2206 diHCl; MK-2206; MK 2206; MK2206 dihydrochloride; MK2206 HCl; MK2206;

    SMILES Code: O=C1NN=C2C3=CC(C4=CC=CC=C4)C(C5=CC=C(C6(N)CCC6)C=C5)N=C3C=CN21.[H]Cl.[H]Cl


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    In Vitro

    Kinase Assay: Akt kinases are assayed by a GSK-derived biotinylated peptide substrate. The extent of peptide phosphorylation is determined by Homogeneous Time Resolved Fluorescence (HTRF) using a lanthanide chelate (Lance)-coupled monoclonal antibody specific for the phosphopeptide in combination with a streptavidin-linked allophycocyanin (SA-APC) fluorophore which will bind to the biotin moiety on the peptide. When the Lance and APC are in proximity, a non-radiative energy transfer takes place from the Lance to the APC, followed by emission of light from APC at 655 nm. Working Solution: 100X protease inhibitor cocktail (PIC): 1mg/mL benzamidine, 0.5 mg/mL pepstatin, 0.5 mg/mL leupeptin, 0.5 mg/mL aprotinin; 10X assay buffer: 500 mM HEPES, pH7.5, 1% PEG, 16.6 mM EDTA, 1 mM EGTA, 1% BSA, 20 mM 9-glycerol phosphate; Quench buffer 50 mM HEPES pH 7.3, 16.6 mM EDTA, 0.1% BSA, 0.1% Triton X-100, 0.17 nM labeled monoclonal antibody, 0.0067 mg/mL SA-APC; ATP/MgCl2 working solution: 1X Assay buffer, 1 mM DTT, 1X PIC, 5% glycerol, active Akt; Peptide working solution: 1X Assay buffer, 1 mM DTT, 1X PIC, 5% glycerol, 2 TM GSK biotinylated peptide. The reaction is assembled by adding 16 µL of ATP/MgCl2 working solution to the appropriate wells. MK-2206 or vehicle (1.0 µL) is added followed by 10 µL of peptide working solution. The reaction is started by adding 13 μL of the enzyme working solution and mixing. The reaction is allowed to proceed for 50 min and then stopped by the addition of 60 µL HTRF quench buffer. The stopped reactions are incubated at room temperature for at least 30 min and then read in the instrument.

     

    Cell Assay: MK-2206 is dissolved in DMSO as a stock solution and diluted by culture media before use. Cells (A431, HCC827, NCI-H292, NCI-H358, NCI-H23, NCI-H1299, Calu-6 and NCI-H460 cells) are seeded at a density of 2-3 × 103 in 96-well plates and incubated for 24 hours. Then MK-2206 (0, 0.3, 1 and 3 μM) is added to the cells. Cell proliferation is determined after 72 or 96 hours.

    MK-2206 is an allosteric inhibitor and is activated by the pleckstrin homology domain. MK-2206 inhibits auto-phosphorylation of both Akt T308 and S473. MK-2206 also prevents Akt-mediated phosphorylation of downstream signaling molecules, including TSC2, PRAS40 and ribosomal S6 proteins. MK-2206 inhibits Ras wild-type (WT) cell lines (A431, HCC827, and NCI-H292) more potently when compared to Ras-mutant cell lines (NCI-H358, NCI-H23, NCI-H1299, and Calu-6). MK-2206 also shows synergistic responses in combination with cytotoxic agents such as erlotinib or lapatinib in lung NCI-H460 or ovarian A2780 tumor cells. MK-2206 or siRNA-mediated Akt inhibition strongly activates autophagy in human glioma cells. However, eukaryotic elongation factor-2 (eEF-2) silencing suppresses MK-2206-induced-autophagy, with a promotion of apoptotic cell death.

    In Vivo

    MK-2206 shows 60% TGI and inhibits more than 70 % of phospho-Akt1/2 (T308 and S473) in A2780 ovarian cancer xenografts at a dose of 240 mg/kg. MK-2206 exhibits significant antitumor activity in NCI-H292 xenograft in combination with erlotinib or lapatinib.

    Animal model

    SK-OV-3, NCI-H292, HCC70, PC-3, and NCI-H460 models in male CD1-nude mice

    Formulation & Dosage

    Dissolved in 30% Captisol; 120 mg/kg; oral administration

    References

    [1] Hirai H, et al. Mol Cancer Therapy, 2010, 9(7), 1956-1967.


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

    MK-2206 2HCl

    Growth-inhibitory effect of MK-2206 on nasopharyngeal carcinoma cell lines. Drug Des Devel Ther. 2014 Oct 10;8:1827-37.

    MK-2206 2HCl

    MK-2206 induces cell cycle arrest at G1 in a dose-dependent manner in CNE-2 and HONE-1 cells. Drug Des Devel Ther. 2014 Oct 10;8:1827-37.

    MK-2206 2HCl

    No apoptosis was induced by MK-2206 in the four nasopharyngeal carcinoma cell lines. Drug Des Devel Ther. 2014 Oct 10;8:1827-37.

    MK-2206 2HCl

    MK-2206 inhibited phosphorylation of AKT downstream targets. SUNE-1 and CNE-2 cells were treated with different concentrations of MK-2206 for 24 hours.  Drug Des Devel Ther. 2014 Oct 10;8:1827-37.

    MK-2206 2HCl

    Effect of MK-2206 on autophagy in human nasopharyngeal carcinoma cells.Drug Des Devel Ther. 2014 Oct 10;8:1827-37.

    MK-2206 2HCl

    Effects of MK-2206 on tumor growth of human CNE-2 xenografts in nude mice. Drug Des Devel Ther. 2014 Oct 10;8:1827-37.

    MK-2206 2HCl

    MK-2206 2HCl

    MK-2206 2HCl


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