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Purity: =100%
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. In cell-free assays, it inhibits Akt1/2/3 with IC50 values of 8 nM, 12 nM, and 65 nM, respectively; it has little to no inhibitory activity against 250 other protein kinases. By preventing Akt's Thr308 and Ser473 phosphorylation, MK-2206 may have anticancer effects. Akt signaling is suppressed by MK-2206, which also promotes cancer cell death when used alone or in combination with other chemotherapeutic drugs. MK-2206 increases sensitivity to rapamycin by enhancing apoptosis and sensitivity to reactive oxygen species.
| Targets |
Akt1 (IC50 = 8 nM); Akt2 (IC50 = 12 nM); Akt3 (IC50 = 65 nM)
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| ln Vitro |
MK-2206 is an allosteric inhibitor and is activated by the pleckstrin homology domain. MK-2206 prevents the auto-phosphorylation of Akt at T308 and S473. Additionally, MK-2206 blocks the Akt-mediated phosphorylation of downstream signaling molecules like TSC2, PRAS40, and ribosomal S6 proteins. [1] MK-2206 inhibits Ras wild-type (WT) cell lines (A431, HCC827, and NCI-H292) more effectively than Ras-mutant cell lines (NCI-H358, NCI-H23, NCI-H1299, and Calu-6). In lung NCI-H460 or ovarian A2780 tumor cells, MK-2206 also exhibits synergistic responses when combined with cytotoxic drugs like erlotinib or lapatinib.[2] MK-2206 or siRNA-mediated Akt inhibition strongly induces autophagy in human glioma cells. However, eukaryotic elongation factor-2 (eEF-2) silencing suppresses MK-2206-induced autophagy while promoting apoptotic cell death.[3]
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| ln 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. In a NCI-H292 xenograft, MK-2206 exhibits significant antitumor activity when combined with erlotinib or lapatinib. [2]
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| Enzyme Assay |
Akt kinases are assayed by a GSK-derived biotinylated peptide substrate. By combining a lanthanide chelate (Lance)-coupled monoclonal antibody that is specific for the phosphopeptide with a streptavidin-linked allophycocyanin (SA-APC) fluorophore that will bind to the peptide's biotin moiety, homogeneous time-resolved fluorescence (HTRF) can be used to determine the degree of phosphorylation. When the Lance and APC are close together, the Lance transfers non-radiative energy to the APC, and the APC then emits light at a wavelength of 655 nm. Protease inhibitor cocktail (PIC) 100X: Benzamidine 1 mg/mL, Pepstatin 0.5 mg/mL, Leupeptin 0.5 mg/mL, Aprotinin 0.5 mg/mL; 10X assay reagent: 20 mM 9-glycerol phosphate, 50 mM HEPES, pH 7.3, 16.6 mM EDTA, 0.1% BSA, 0.1% Triton X-100, 0.17 nM labeled monoclonal antibody, and 0.0067 mg/mL SA-APC make up the quench buffer. Working solution for the ATP/MgCl2 assay: 1X Assay buffer, 1 mM DTT, 1X PIC, 5% glycerol, active Akt; Peptide working solution: 2 TM GSK biotinylated peptide, 1X Assay buffer, 1 mM DTT, 1X PIC, and 5% glycerol. 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.
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| Cell Assay |
In 96-well plates, 2-3 × 103 cells are seeded, and the plates are then incubated for 24 hours. After that, the cells receive additions of MK-2206 (0, 0.3, 1 and 3 μM). 72 or 96 hours later, cell proliferation is assessed.
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| Animal Protocol |
SK-OV-3, NCI-H292, HCC70, PC-3, and NCI-H460 models in male CD1-nude mice
120 mg/kg Orally administered |
| References |
| Molecular Formula |
C25H23CL2N5O
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|---|---|
| Molecular Weight |
480.39
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| Exact Mass |
479.127
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| Elemental Analysis |
C, 62.24; H, 5.22; Cl, 14.70; N, 14.52; O, 3.32
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| CAS # |
1032350-13-2
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| Related CAS # |
MK-2206 free base;1032349-93-1;MK-2206;1032349-77-1
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| Appearance |
Yellow solid powder
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| LogP |
6.547
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| SMILES |
O=C1N([H])N=C2C3=C([H])C(C4C([H])=C([H])C([H])=C([H])C=4[H])=C(C4C([H])=C([H])C(=C([H])C=4[H])C4(C([H])([H])C([H])([H])C4([H])[H])N([H])[H])N=C3C([H])=C([H])N21
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| InChi Key |
HWUHTJIKQZZBRA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H21N5O.2ClH/c26-25(12-4-13-25)18-9-7-17(8-10-18)22-19(16-5-2-1-3-6-16)15-20-21(27-22)11-14-30-23(20)28-29-24(30)31;;/h1-3,5-11,14-15H,4,12-13,26H2,(H,29,31);2*1H
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| Chemical Name |
8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one;dihydrochloride
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| Synonyms |
MK2206 HCl; MK2206 dihydrochloride; MK2206; MK 2206; MK-2206
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~14 mg/mL (~29.1 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (3.48 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.67 mg/mL (3.48 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: 15% Captisol: 17mg/mL Solubility in Formulation 4: 25 mg/mL (52.04 mM) in 20% SBE-β-CD in Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0816 mL | 10.4082 mL | 20.8164 mL | |
| 5 mM | 0.4163 mL | 2.0816 mL | 4.1633 mL | |
| 10 mM | 0.2082 mL | 1.0408 mL | 2.0816 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Growth-inhibitory effect of MK-2206 on nasopharyngeal carcinoma cell lines.Drug Des Devel Ther. 2014 Oct 10;8:1827-37. |
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. |
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 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. |
Effect of MK-2206 on autophagy in human nasopharyngeal carcinoma cells.Drug Des Devel Ther. 2014 Oct 10;8:1827-37. |
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. |
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