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MK-2206 dihydrochloride Chemical Structure
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Biological Activity
| Information | MK-2206 is a highly selective inhibitor of Akt1, Akt2 and Akt3 with IC50 of 8 nM, 12 nM and 65 nM, respectively. | |||||
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| Targets | Akt1 | Akt2 | Akt3 | |||
| IC50 | 8 nM | 12 nM | 65 nM [1]
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| In vitro | 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. [1] 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. [2] MK-2206 or siRNA-mediated Akt inhibition strongly activates autophagy in human glioma cells. While eukaryotic elongation factor-2 (eEF-2) silencing could suppress MK-2206-induced-autophagy, with a promotion of apoptotic cell death. [3] | |||||
| 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. [1] MK-2206 exhibits significant antitumor activity in NCI-H292 xenograft in combination with erlotinib or lapatinib. [2] | |||||
| Clinical Trials | MK-2206 is currently under Phase II clinical trial for treatment of ovarian cancer, primary peritoneal cancer and fallopian tube cancer. | |||||
| Features | MK-2206 is the first allosteric small molecule inhibitor of Akt to enter clinical development. | |||||
Protocol
Kinase Assay: [4]
| Akt kinases 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. |
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Cell Assay: [2]
| Cell lines: | A431, HCC827, NCI-H292, NCI-H358, NCI-H23, NCI-H1299, Calu-6, and NCI-H460 cells |
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| Concentrations: | 0, 0.3, 1, and 3 μM |
| Incubation Time: | 72 or 96 hours |
| Method: | MK-2206 is dissolved in DMSO as a stock solution and diluted by culture media before use. 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. |
Animal Study:[2]
| Animal Models: | SK-OV-3, NCI-H292, HCC70, PC-3, and NCI-H460 models in male CD1-nude mice |
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| Formulation: | Formulated in 30% Captisol |
| Dosages: | 120 mg/kg |
| Administration: | Orally administered |
Chemical Information
| Molecular Weight (WM): | 480.39 |
|---|---|
| Formula: | C25H21N5O.2HCl |
| CAS No.: | 1032350-13-2 |
| Synonyms: |
N/A
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| Dissolve in (25°C): | DMSO ≥96mg/mL |
| Water ≥96mg/mL | |
| Ethanol ≥2mg/mL | |
| Storage: | 2 years-20°CPowder |
| 1 week-4°Cin DMSO | |
| 1 month-80°in DMSO |
Quality Control & MSDS
Research Area
Notes:
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Selleck's high quality products have been used in several published research findings, including the following:
Combinatorial Treatments That Overcome PDGFRb-Driven Resistance of Melanoma Cells to V600EB-RAF Inhibition
Phosphoproteomic Analysis of Salmonella-Infected Cells Identifies Key Kinase Regulators and SopB-Dependent Host Phosphorylation Events
The Anandamide effect on NO/cGMP pathway in human platelets.
Radiation-induced Akt activation modulates radioresistance in human glioblastoma cells.
Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator
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Confocal microscopy images of NO formation. DAF 2 DA-loaded washed platelets (1.0109 platelets/mL) were preincubated at 378C with saline (A), and then stimulated for 1min with 0.1 (B), 1.0 (C) or 10 (D) mM AEA. In Panel (E–F–G) washed platelets were preincubated with 1 mM SR1 (E), 1 Mm MK2206 (F) or 20 mM LY294002 (G), and then stimulated for 1min with 1.0 mM AEA. In panel (H) is reported the effect of 5 mg/mL collagen, used as a positive control. All the experiments were carried out in the presence of 100 mM L-arginine. NO formation was visualized by confocal microscropy as detailed in Methods.
Confocal microscopy images of NO formation. DAF 2 DA-loaded washed platelets (1.0109 platelets/mL) were preincubated at 378C with saline (A), and then stimulated for 1min with 0.1 (B), 1.0 (C) or 10 (D) mM AEA. In Panel (E–F–G) washed platelets were preincubated with 1 mM SR1 (E), 1 Mm MK2206 (F) or 20 mM LY294002 (G), and then stimulated for 1min with 1.0 mM AEA. In panel (H) is reported the effect of 5 mg/mL collagen, used as a positive control. All the experiments were carried out in the presence of 100 mM L-arginine. NO formation was visualized by confocal microscropy as detailed in Methods.
Data from [Journal of Cellular Biochemistry 2010.December;112:924–932] MK-2206 dihydrochloride purchased from Selleck
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C.U87MG cells were treated with vehicle or 1 μM MK-2206 for 1 hr, and then irradiated with 6 Gy. Total cell lysate was harvested 1 hr after IR and subjected to Western blot analysis with the indicated antibody. Cells without IR treatment were used as a control.
D. Cells were treated with vehicle (control) or 1 μM MK-2206 for 1 hr, then irradiated with indicated dosage. 4 hr after IR, cells were fed with drug-free medium, and incubated for another 20 hr at 37°C, after which they were trypsinized and seeded for clonogenic survival assay. Colony-forming efficiency was determined 14 d later. C.U87MG cells were treated with vehicle or 1 μM MK-2206 for 1 hr, and then irradiated with 6 Gy. Total cell lysate was harvested 1 hr after IR and subjected to Western blot analysis with the indicated antibody. Cells without IR treatment were used as a control.
D. Cells were treated with vehicle (control) or 1 μM MK-2206 for 1 hr, then irradiated with indicated dosage. 4 hr after IR, cells were fed with drug-free medium, and incubated for another 20 hr at 37°C, after which they were trypsinized and seeded for clonogenic survival assay. Colony-forming efficiency was determined 14 d later.Data from [Radiation Oncology 2009.October;4:43] MK-2206 dihydrochloride purchased from Selleck
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The AEA effect on eNOS phosphorylation. Washed platelets (1.0109 platelets/mL), preincubated at 378C with saline, 1 mM SR1, 1mM SR2, 20 mM LY294002, 1mM MK2206, 1.0mM EGTA, or 30 mM BAPTA/AM, were stimulated for 1 min with 1.0 mM AEA. At the end of incubation suitable aliquots were immunoblotted with anti-p-eNOSser1177 as detailed in Methods.Blots are representative of five independent experiments.
The AEA effect on eNOS phosphorylation. Washed platelets (1.0109 platelets/mL), preincubated at 378C with saline, 1 mM SR1, 1mM SR2, 20 mM LY294002, 1mM MK2206, 1.0mM EGTA, or 30 mM BAPTA/AM, were stimulated for 1 min with 1.0 mM AEA. At the end of incubation suitable aliquots were immunoblotted with anti-p-eNOSser1177 as detailed in Methods.Blots are representative of five independent experiments.
Data from [Journal of Cellular Biochemistry 2010.December;112:924–932] MK-2206 dihydrochloride purchased from Selleck
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Mean IL-8 concentrations determined by ELISA of the supernatants of HeLa cells infected with wild-type Salmonella. Kinase inhibitors are indicated on the x axis, and the target families of the inhibitors are indicated above each column. CEC, chelerythrine; Pim Inh, Pim-1 inhibitor 2. Inhibitors that significantly affected IL-8 production relative to the control (P < 0.05, Bonferroni post hoc test from one-way ANOVA) are indicated with an asterisk. Relative cell viability is also shown, as determined by reduction of XTT by viable cells. A450, absorbance at 450 nm. - Mean IL-8 concentrations determined by ELISA of the supernatants of HeLa cells infected with wild-type Salmonella. Kinase inhibitors are indicated on the x axis, and the target families of the inhibitors are indicated above each column. CEC, chelerythrine; Pim Inh, Pim-1 inhibitor 2. Inhibitors that significantly affected IL-8 production relative to the control (P < 0.05, Bonferroni post hoc test from one-way ANOVA) are indicated with an asterisk. Relative cell viability is also shown, as determined by reduction of XTT by viable cells. A450, absorbance at 450 nm.
Data from [Sci Signal 2011 Sep;4:rs9] MK-2206 dihydrochloride purchased from Selleck
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After starved in serum-free medium for 24h, Breast cancer cells incubated with the indicated concentrations of MK-2206 for 3h,followed by 15-minute stimolation of 100ng/ml EGF.
After starved in serum-free medium for 24h, Breast cancer cells incubated with the indicated concentrations of MK-2206 for 3h,followed by 15-minute stimolation of 100ng/ml EGF.
Data independently produced by Dr Zhang of Tianjin Medical University MK-2206 dihydrochloride purchased from Selleck
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Effect of selected agents on NOx and cGMP formation induced by AEA. Washed platelets (1.0109 platelets/mL), prewarmed at 378C with saline or 1mM SR1, 1mM SR2, 20 mMURB597 (URB), 1mMMK2206 (MK) or 20 mMLY294002 (LY), were incubated for 1min with 100 mML-arginine in the presence of 1.0 mMAEA. NOx (panel A) and cGMP (panel B) content were determined as detailed in Methods. Each bar represents the meanSD of five independent experiments carried out in triplicate. Student’s t-test: P <0.0001 versus none;P <0.0005; §P <0.005 versus AEA
Effect of selected agents on NOx and cGMP formation induced by AEA. Washed platelets (1.0109 platelets/mL), prewarmed at 378C with saline or 1mM SR1, 1mM SR2, 20 mMURB597 (URB), 1mMMK2206 (MK) or 20 mMLY294002 (LY), were incubated for 1min with 100 mML-arginine in the presence of 1.0 mMAEA. NOx (panel A) and cGMP (panel B) content were determined as detailed in Methods. Each bar represents the meanSD of five independent experiments carried out in triplicate. Student’s t-test: P <0.0001 versus none;P <0.0005; §P <0.005 versus AEA
Data from [Journal of Cellular Biochemistry 2010.December;112:924–932] MK-2206 dihydrochloride purchased from Selleck
- It is great to hear from you and I am very happy to work with you and selleck. From our experience all the inhibitors works very well and we are very satisfied with the quality of the product. In addition, the shipping is on time and we are delight that have selleck as our research parter.
Qingsong Liu, Ph.DProf. Nathanael Gray Lab Dana-Farber Cancer Institute Biological Chemistry and Molecular Pharmacology Harvard Medical School
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Confocal microscopy images of NO formation. DAF 2 DA-loaded washed platelets (1.0109 platelets/mL) were preincubated at 378C with saline (A), and then stimulated for 1min with 0.1 (B), 1.0 (C) or 10 (D) mM AEA. In Panel (E–F–G) washed platelets were preincubated with 1 mM SR1 (E), 1 Mm MK2206 (F) or 20 mM LY294002 (G), and then stimulated for 1min with 1.0 mM AEA. In panel (H) is reported the effect of 5 mg/mL collagen, used as a positive control. All the experiments were carried out in the presence of 100 mM L-arginine. NO formation was visualized by confocal microscropy as detailed in Methods.
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Data from [Journal of Cellular Biochemistry 2010.December;112:924–932]
C.U87MG cells were treated with vehicle or 1 μM MK-2206 for 1 hr, and then irradiated with 6 Gy. Total cell lysate was harvested 1 hr after IR and subjected to Western blot analysis with the indicated antibody. Cells without IR treatment were used as a control. D. Cells were treated with vehicle (control) or 1 μM MK-2206 for 1 hr, then irradiated with indicated dosage. 4 hr after IR, cells were fed with drug-free medium, and incubated for another 20 hr at 37°C, after which they were trypsinized and seeded for clonogenic survival assay. Colony-forming efficiency was determined 14 d later.
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Data from [Radiation Oncology 2009.October;4:43]
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