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| Molecular formula | C25H21N5O |
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Compound Overview
MK-2206 free base is an orally active pan-AKT inhibitor, with IC50 values of 8 nM, 12 nM, and 65 nM against AKT1, AKT2, and AKT3, respectively. It inhibits the Akt/mTOR signaling pathway and reduces downstream GSK3β and Mcl-1 levels via proteasomal degradation, inducing G1-phase cell cycle arrest, apoptosis, epithelial-mesenchymal transition, fibroblast activation, and extracellular matrix deposition. It also causes transient hyperglycemia and hyperinsulinemia in animals, and can be used in research related to solid tumors, renal fibrosis, and hypercholesterolemia[1][2][3][4]. It has the molecular formula C25H21N5O and a molecular weight of 407.47 g/mol.
Physical & Chemical Properties
| CAS Number | 1032349-93-1 |
|---|---|
| Molecular Formula | C25H21N5O |
| Molecular Weight | 407.47 g/mol |
| SMILES | O=C1N2C(C3=CC(C4=CC=CC=C4)=C(C(C=C5)=CC=C5C6(CCC6)N)N=C3C=C2)=NN1 |
| Target | Akt1, Akt2, Akt3 |
| Signaling Pathway | PI3K/Akt/mTOR; Apoptosis; Stem Cell/Wnt |
| Storage | Please store the product under the recommended conditions in the Certificate of Analysis. |
| Shipping | Room temperature in continental US; may vary elsewhere. |
Biological Activity
IC50 & Target[1]
|
Akt1 8 nM (IC50) |
Akt2 12 nM (IC50) |
Akt3 65 nM (IC50) |
Literature Cited
Sources cited in this description and in the In Vitro & In Vivo Data tab. Peer-reviewed publications that used this product are listed under References.
[1]. Yan L. Abstract# DDT01-1: MK-2206: A potent oral allosteric AKT inhibitor. Cancer research. 2009 May 1;69(9_Supplement):DDT01-1.
Safety
For Research Use Only. Not for use in diagnostic or therapeutic procedures, and not for human or veterinary use. Handle in accordance with your institution's chemical hygiene plan.
In Vitro
Akt1 kinase activity in various human cancer cell lines is inhibited by MK-2206 free base with an IC50 of approximately 20 nM; the downstream signaling pathway of Akt is blocked, potent antiproliferative effects are exerted on cancer cell lines with specific PI3K pathway gene defects, and activation of the Ras pathway predicts no response[1]. In relevant human cancer cell lines, combining MK-2206 free base with various chemotherapeutic agents and targeted inhibitors produces additive or synergistic antiproliferative and pro-apoptotic sensitizing effects[1]. Growth of the U937, OCI/AML3, MV-4-11 and MOLM-13 cell lines, all of acute myeloid leukemia (AML), is potently inhibited by MK-2206 (72 h) free base, with IC50 values spanning 0.6 to 2.5 μM; cytotoxicity toward normal human peripheral blood mononuclear cells (PBMCs) is only extremely low[2]. G1 cell cycle arrest, dose-dependent, is induced in OCI/AML3, MOLM-13 and MV-4-11 AML cell lines by MK-2206 (1-10 μM; 24 h) free base[2]. In OCI/AML3, MOLM-13 and MV-4-11 cells, which are acute myeloid leukemia (AML) cell lines, apoptosis is triggered dose-dependently by MK-2206 (1-10 μM; 24 h) free base, and apoptotic cell populations expand significantly at higher doses[2]. In MV-4-11 acute myeloid leukemia (AML) cells, MK-2206 (0.1-10 μM; 2-24 h) free base brings about apoptosis through caspase-3 and PARP cleavage; Mcl-1 protein levels in MV-4-11, OCI/AML3 and U937 AML cells are downregulated dose-dependently, and phosphorylation of Akt at Ser473 and GSK3β at Ser9 is inhibited after 2 to 24 h of treatment, respectively[2]. Via a GSK3β-mediated proteasome-dependent mechanism, Mcl-1 is downregulated by MK-2206 (10 μM; 1-4 h) free base in MV-4-11 acute myeloid leukemia (AML) cells[2]. In the acute myeloid leukemia (AML) cell lines MV-4-11, MOLM-13 and OCI/AML3, cytotoxicity is synergistically enhanced when MK-2206 (200 nM; 72 h) free base is given together with Cytarabine (ED50 CI value < 1); in U937 AML cells, however, the combination has antagonistic effects (ED50 CI value = 1.13)[2]. In HK-2 cells, MK-2206 (0.5-5 μM; 48 h) free base suppresses TGF-β1-induced fibrosis, epithelial-mesenchymal transition (EMT), and Akt/mTOR signaling pathway activation. At the effective concentration of 1 μM, mRNA expression of Collagen I and Fibronectin is reduced, E-cadherin levels are restored, and expression of mesenchymal markers and phosphorylated Akt/mTOR proteins is suppressed[3]. LDLR protein levels in HepG2 cells subjected to sterol feeding or sterol starvation are upregulated by MK-2206 (0.5-20 μM; 2-24 h) free base. In the sterol starvation group, the maximum induction is seen after 14 h at 5 μM, whereas the sterol feeding group reaches its maximum with 10 μM for 14 h. A significant induction effect furthermore appears within 4 h of 5 μM treatment[4]. In sterol-fed HepG2 cells, AKT kinase activity is inhibited by MK-2206 (2.5-5 μM; 2-6 h) free base. Concentrations of ≥2.5 μM lower the phosphorylation levels of AKT and of PRAS40, its downstream target, within 2 h[4]. Under both sterol-fed and sterol-starved conditions, HepG2 cells show greater cell-surface LDLR expression and stimulated LDL uptake with MK-2206 (5 μM; 14 h) free base[4]. Within 2 h, LDLR mRNA expression is induced in sterol-fed HepG2 cells by MK-2206 (5-12 μM; 2-24 h) free base; the mechanism enhances transcription (rather than mRNA stabilization) and does not depend on de novo protein synthesis[4]. In sterol-fed IHH, HeLa, IMH, and Hepac1c7 cells, LDLR protein levels rise under MK-2206 (5-10 μM; 14 h) free base[4]. De novo cholesterol biosynthesis is inhibited by MK-2206 (5 μM; 24 h) free base in HepG2 cells under sterol starvation conditions[4]. In CHO cells and HMGCR-deficient UT-2 cells, LDLR protein levels are upregulated by MK-2206 (5 μM; 14 h) free base, indicating independence of this effect from HMGCR activity[4]. In sterol-starved HepG2 cells, the LDLR (low-density lipoprotein receptor)-inducing effect of Mevastatin is enhanced by MK-2206 (0.5-4 μM; 38 h) free base[4]. In sterol-fed HepG2 cells, MK-2206 (5 μM; 2-24 h) free base raises mRNA expression of PCSK9, HMGCR, SREBP-2 and HMGCS1, while ACACA, FASN and SCD1 are affected only minorly and IDOL is not affected at all[4]. LDLR promoter activity in sterol-fed HepG2 cells is stimulated by MK-2206 (2.5-5 μM; 14-24 h) free base, and this depends on SRE-1[4]. LDLR mRNA levels in sterol-fed HepG2 cells are upregulated by MK-2206 (5 μM; 14-24 h) free base through an SREBP-2-dependent route[4]. In sterol-fed HepG2 cells, proteolytic cleavage of FL-SREBP-2, which generates the active NTF-SREBP-2, is stimulated by MK-2206 (5 μM; 2-6 h) free base[4]. LDLR protein levels in primary adult hepatocytes are upregulated by MK-2206 (2.5-10 μM; 14 h) free base[4].
Cell Cycle Analysis[2]
| Cell Line | OCI/AML3, MOLM-13, MV-4-11 human AML cell lines |
|---|---|
| Concentration | 1, 5 and 10 μM |
| Incubation Time | 24 h |
| Result | Caused a dose-dependent increase in the percentage of cells in the G1 phase and a corresponding decrease in cells in the S and G2/M phases across all three cell lines. Increased G1 phase cells in OCI/AML3 cells from ~45% (control) to ~75% (10 μM MK-2206). Increased G1 phase cells in MOLM-13 cells from ~45% to ~75%. Increased G1 phase cells in MV-4-11 cells from ~60% to ~90%. |
Apoptosis Analysis[2]
| Cell Line | OCI/AML3, MOLM-13, MV-4-11 human AML cell lines |
|---|---|
| Concentration | 1-10 μM |
| Incubation Time | 24 h |
| Result | Caused a dose-dependent increase in the percentage of apoptotic cells in all three cell lines. Increased apoptotic cells in OCI/AML3 cells from ~4% (control) to ~11.5% (10 μM MK-2206). Increased apoptotic cells in MOLM-13 cells from ~3% to ~9.5%. Increased apoptotic cells in MV-4-11 cells from ~0.5% to ~14.5%. |
Western Blot Analysis[2]
| Cell Line | MV-4-11, OCI/AML3, U937 human AML cell lines |
|---|---|
| Concentration | 0.1, 1, 5 and 10 μM (24 h incubation in MV-4-11 cells); 0.1, 1, 5 and 10 μM (2 h incubation in MV-4-11, OCI/AML3, U937 cells) |
| Incubation Time | 24 h (MV-4-11 cells); 2 h (MV-4-11, OCI/AML3, U937 cells) |
| Result | Induced dose-dependent cleavage of caspase-3 and PARP, and reduced Mcl-1 protein levels to 51% of control at 10 μM in MV-4-11 cells treated for 24 h, with no effect on Bak, Bcl-2, or Bcl-XL levels. Reduced Akt phosphorylation at Ser473, reduced GSK3β phosphorylation at Ser9, and reduced Mcl-1 protein levels to 35% of control in MV-4-11, 26% in OCI/AML3, and 33% in U937 at 10 μM in cells treated for 2 h, with no effect on total Akt, total GSK3β, Bcl-2, or Bcl-XL levels. |
Real Time qPCR[2]
| Cell Line | MV-4-11 human AML cell line |
|---|---|
| Concentration | 0.1, 1, 5 and 10 μM |
| Incubation Time | 24 h |
| Result | Had no significant effect on Mcl-1 mRNA transcript levels in MV-4-11 cells at any tested concentration. |
Western Blot Analysis[2]
| Cell Line | MV-4-11 human AML cell line |
|---|---|
| Concentration | 10 μM MK-2206 (following 30 min pretreatment with 10 μM MG-132 or 20 mM lithium chloride) |
| Incubation Time | 1 h, 2 h, 4 h |
| Result | Pretreatment with MG-132 prevented MK-2206-associated downregulation of Mcl-1, maintaining Mcl-1 levels at near-control values across all incubation times. Pretreatment with lithium chloride prevented MK-2206-induced Mcl-1 downregulation and maintained GSK3β phosphorylation at Ser9 at levels comparable to control cells. |
Cell Viability Assay[2]
| Cell Line | U937, OCI/AML3, MV-4-11, MOLM-13 human AML cell lines |
|---|---|
| Concentration | 200 nM MK-2206 (co-administered with varying cytarabine concentrations) |
| Incubation Time | 72 h |
| Result | Significantly reduced the IC50 of cytarabine in MV-4-11, OCI/AML3, and MOLM-13 cells, but not in U937 cells. Produced ED50 CI values of 0.59 (MV-4-11), 0.37 (MOLM-13), 0.38 (OCI/AML3), and 1.13 (U937), indicating synergistic effects in the first three cell lines and an antagonistic effect in U937 cells. |
Western Blot Analysis[4]
| Cell Line | human hepatoma HepG2 cells (sterol-fed and sterol-starved conditions) |
|---|---|
| Concentration | 0.5, 1, 2.5, 5, 10 and 20 μM (for 14 h); 5 μM (for time-course analysis) |
| Incubation Time | 14 h (dose-response); 2-24 h (time-course with 5 μM) |
| Result | Induced LDLR protein expression in a dose-responsive manner, with 5 μM and 10 μM exerting maximal effects in sterol-starved and sterol-fed cells, respectively; concentrations above 10 μM mitigated the LDLR-inducing effect. Significantly increased LDLR levels within 4 h of 5 μM treatment, reaching maximum levels at 14 h (sterol-starved) and 18 h (sterol-fed), followed by a slight decline by 24 h. |
Western Blot Analysis[4]
| Cell Line | sterol-fed human hepatoma HepG2 cells |
|---|---|
| Concentration | 2.5, 5 μM (for 2 h); 2.5, 5 μM (for 6 h) |
| Incubation Time | 2 h; 6 h |
| Result | Potently inhibited AKT activity, as shown by reduced pAKT and pPRAS40 levels within 2 h of treatment with concentrations as low as 2.5 μM. |
Real Time qPCR[4]
| Cell Line | sterol-fed human hepatoma HepG2 cells |
|---|---|
| Concentration | 5 μM |
| Incubation Time | 2-24 h; 12 h (followed by actinomycin D treatment for 2-6 h); 5 h (with 1 h cycloheximide preincubation) |
| Result | Induced LDLR mRNA levels in a time-dependent manner, with significant increases observed within 2 h of treatment. Had no significant stabilizing effect on LDLR mRNA. Inhibition of protein synthesis with cycloheximide did not reduce MK-2206-mediated induction of LDLR mRNA. |
Western Blot Analysis[4]
| Cell Line | sterol-fed immortalized human hepatocytes (IHH), HeLa, immortalized mouse hepatocytes (IMH), and Hepac1c7 cells |
|---|---|
| Concentration | 5, 10 μM |
| Incubation Time | 14 h |
| Result | Induced LDLR protein expression in all tested cell lines, with significant increases observed at 5 μM and 10 μM. |
Western Blot Analysis[4]
| Cell Line | Chinese hamster ovary (CHO) cells and UT-2 cells (HMGCR-deficient CHO cells) |
|---|---|
| Concentration | 5 μM |
| Incubation Time | 14 h |
| Result | Induced LDLR protein expression in both CHO and UT-2 cells, with significant increases relative to vehicle-treated cells. |
Western Blot Analysis[4]
| Cell Line | sterol-starved human hepatoma HepG2 cells treated with mevastatin |
|---|---|
| Concentration | 0.5, 1, 2, 4 μM |
| Incubation Time | 14 h (following 24 h mevastatin pretreatment) |
| Result | Combination treatment with MK-2206 and mevastatin markedly increased LDLR protein levels relative to treatment with either agent alone. |
Real Time qPCR[4]
| Cell Line | sterol-fed human hepatoma HepG2 cells |
|---|---|
| Concentration | 5 μM |
| Incubation Time | 2-24 h |
| Result | Induced mRNA expression of PCSK9, HMGCR, SREBP-2, and HMGCS1 in a time-dependent manner, with significant increases observed at multiple time points. Had no effect on IDOL mRNA levels, and only modestly induced ACACA, FASN, and SCD1 mRNA levels with significant increases at 8 h. |
Real Time qPCR[4]
| Cell Line | sterol-fed human hepatoma HepG2 cells with SREBP-2 knockdown |
|---|---|
| Concentration | 5 μM |
| Incubation Time | 14 h (24 h post-transfection) |
| Result | Knockdown of SREBP-2 significantly diminished the LDLR-inducing effect of MK-2206 on LDLR mRNA levels. |
Western Blot Analysis[4]
| Cell Line | sterol-fed human hepatoma HepG2 cells |
|---|---|
| Concentration | 5 μM |
| Incubation Time | 2, 4, 6 h |
| Result | Increased levels of CTF-SREBP-2 (membrane fraction) and NTF-SREBP-2 (nuclear extract), with a concomitant reduction in FL-SREBP-2 levels, indicating enhanced proteolytic cleavage of SREBP-2. |
In Vivo
In preclinical ovarian cancer xenograft models, MK-2206 free base boosts the antitumor efficacy of multiple chemotherapeutic agents; it also causes mild, transient hyperglycemia and hyperinsulinemia in animals, which resolves after treatment[1]. In mice, MK-2206 free base (120 mg/kg; p.o.; alternate days; 4 total doses) alleviates UUO-induced renal fibrosis by reducing inflammation, inhibiting epithelial-mesenchymal transition, and suppressing both myofibroblast activation and extracellular matrix deposition, as well as by blocking activation of the Akt/mTOR signaling pathway[3].
| Animal Model | strain not specified (n=6 per group)[3] |
|---|---|
| Dosage | 120 mg/kg |
| Administration | p.o.; alternate days; 4 total doses |
| Result | Reduced renal tubular injury and interstitial collagen fiber deposition compared to untreated UUO mice. Lowered renal mRNA expression of inflammatory factors TGF-β1, IL-1β, and IL-6. Restored renal E-cadherin expression, reduced expression of myofibroblast markers α-SMA and Vimentin, and downregulated EMT-associated transcription factors Twist and Snail in UUO kidneys. Decreased renal protein expression of extracellular matrix components Collagen I and Fibronectin. Inhibited UUO-induced phosphorylation of Akt and mTOR in kidney tissue, reducing the p-Akt/Akt ratio and p-mTOR/mTOR ratio compared to untreated UUO mice. |
Data provided by the manufacturer. Numbered citations refer to the Literature Cited list in the product description.
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