MK256
MK256 is an orally active, selective CDK8 inhibitor and CDK19/cyclin C inhibitor with IC50 values of 2.5 nM and 3.3 nM, respectively. MK256 downregulates phosphorylated STAT1 (S727), STAT5 (S726), MCL-1 mRNA and CCL2 mRNA. MK256 exhibits anti-tumor activity in acute myeloid leukemia. MK256 can be used for the research of acute myeloid leukemia.
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- No. CAS: 2271348-04-8
- Fòrmula: C14H9BrN2O2
- Peso molecular:317.14
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Almacenamiento:
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Actividad biológica
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CDK8/cyclin C 2.5 nM (IC50) |
CDK19/CycC 3.3 nM (IC50) |
STAT1 |
STAT5 |
Mcl-1 |
MK256 is a potent and selective cell-free CDK8/cyclin C inhibitor (IC50 = 2.5 nM) and CDK19/cyclin C inhibitor (IC50 = 3.3 nM), with approximately 40-fold reduced potency against the closest off-target CDK9[1].
MK256 (50-500 nM; 6 days) induces dose-dependent differentiation of CD34+/CD38− AML TEX leukemia stem cells, which is confirmed by the decreased expression of stem cell markers (CD34, CD93) and increased expression of differentiation markers (CD38, CD117) after 6 days of treatment[1].
MK256 (administered for 7 consecutive days) inhibits the proliferation of AML cell lines in vitro with differential potency; it exhibits the strongest activity against MV-4-11 (IC50 = 23 nM) and MOLM-14 (IC50 = 24 nM) cells, which have high baseline levels of phosphorylated STAT1 (S727) and STAT5 (S726)[1].
MK256 (300-1000 nM) downregulates the expression of CCL2 mRNA in MOLM-14, MV-4-11 and KG-1 acute myeloid leukemia (AML) cell lines, and also downregulates the expression of MCL-1 mRNA in KG-1 cells and MOLM-14 cells treated with high concentrations[1].
MK256 (0.3-3000 nM; 2-48 h) downregulates serine-phosphorylated STAT1, STAT3 and STAT5, reduces MCL-1 levels, and induces apoptosis in MV-4-11 and MOLM-14 AML cell lines in a dose- and time-dependent manner, with no effect on tyrosine-phosphorylated STAT[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:CD34+/CD38- AML TEX leukemia stem cells
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Concentration:50 nM; 500 nM
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Incubation Time:6 days
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Result:Induced mild differentiation at 50 nM, while produced a stronger effect at 500 nM.
Reduced CD34 expression by 13% (from 59.0% to 51.4%) at 50 nM.
Reduced CD93 expression by 6.5% (from 80.4% to 75.2%) at 50 nM.
Increased CD38 expression from 39.5% to 79.3% at 50 nM.
Increased CD117 expression by 16.5% (from 73.2% to 85.3%) at 50 nM.
Reduced CD34 expression by 28% (from 59.0% to 42.5%) at 500 nM.
Reduced CD93 expression by ~30% (from 80.4% to 58.3%) at 500 nM.
Increased CD38 expression from 39.5% to 70.9% at 500 nM.
Increased CD117 expression by 8.6% (from 73.2% to 79.5%) at 500 nM.
Left CD96 expression unchanged with both concentrations.
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Cell Line:MV-4-11 and MOLM-14 AML cell lines
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Concentration:MV-4-11: 30 nM, 100 nM, 300 nM, 1000 nM (48 h); MOLM-14: 0.3 nM, 1 nM, 3 nM, 10 nM, 30 nM, 100 nM, 300 nM (2 h); 300 nM (2 h, 4 h, 24 h); 30 nM, 100 nM, 300 nM, 1000 nM, 3000 nM (48 h)
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Incubation Time:MV-4-11: 48 h; MOLM-14: 2 h, 4 h, 24 h, 48 h
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Result:Caused dose-dependent reductions in p-STAT1(S727), p-STAT3(S727), p-STAT5(S726), and MCL-1 in MV-4-11 cells after 48 h treatment, with complete abrogation of p-STAT1(S727) at 1000 nM; left p-STAT1(Y701) and p-STAT5(Y694) unaffected.
Caused dose-dependent reductions in p-STAT1(S727), p-STAT3(S727), p-STAT5(S726), and MCL-1 in MOLM-14 cells after 2 h treatment.
Showed time-dependent reductions in p-STAT1(S727), p-STAT3(S727), and p-STAT5(S726) over 24 h, with increased MCL-1 expression over time in MOLM-14 cells treated with 300 nM.
Caused dose-dependent reductions in p-STAT1(S727), p-STAT3(S727), p-STAT5(S726), and MCL-1, plus dose-dependent increases in cleaved PARP and cleaved Caspase 3 in MOLM-14 cells after 48 h treatment; unexpectedly upregulated BCL-2 expression.
When administered in combination with Venetoclax (HY-15531) at 25 mg/kg once daily at doses of 10 mg/kg or 50 mg/kg, MK256 (10-50 mg/kg; p.o.; once daily; 5 days on/2 days off schedule) enhances the anti-tumor growth efficacy of Venetoclax against AML tumors in the MOLM-14 xenograft model, with the tumor growth inhibition rate reaching 70% in the 50 mg/kg dose group[1].
MK256 (10-100 mg/kg; p.o.; single administration) dose-dependently downregulates phosphorylated STAT1S727, STAT3S727 and STAT5S726 in MOLM-14 AML xenografts[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:NOD SCID (female, MOLM-14 AML cells injected subcutaneously, tumors grown to ~200 mm3 before treatment)[1]
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Dosage:50 mg/kg
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Administration:p.o.; twice daily; 5 days on/2 days off for three weeks
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Result:Reduced average tumor volume from ~300 mm3 to 200 mm3 by day 22, compared to 1600 mm3 in controls.
Reduced average tumor weight to 0.16 g, compared to 1.85 g in controls.
Downregulated phosphorylated STAT1(S727) and STAT5(S726) in harvested tumors.
Increased average body weight from 23.5 g to 23.9 g, indicating good tolerability.
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Animal Model:NOD SCID (female, MOLM-14 AML cells injected subcutaneously, tumors grown to ~200 mm3 before treatment)[1]
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Dosage:10 mg/kg (in combination with venetoclax 25 mg/kg); 50 mg/kg (in combination with venetoclax 25 mg/kg)
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Administration:p.o.; once daily; 5 days on/2 days off schedule
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Result:Enhanced venetoclax-induced tumor growth inhibition from 15% to 33% at 10 mg/kg dose.
Enhanced venetoclax-induced tumor growth inhibition to 70% at 50 mg/kg dose.
Caused 20% weight loss in mice treated with 50 mg/kg plus venetoclax.
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Animal Model:NOD SCID (female, MOLM-14 AML cells injected subcutaneously, tumors grown to at least 100 mm3 before treatment)[1]
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Dosage:10 mg/kg; 50 mg/kg; 100 mg/kg
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Administration:p.o.; single dose
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Result:Caused dose-dependent downregulation of phosphorylated STAT1(S727), STAT3(S727), and STAT5(S726) in tumor tissue, with higher doses producing greater inhibition.
Chemical Information
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No. CAS 2271348-04-8
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Peso molecular 317.14
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Fòrmula C14H9BrN2O2
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SMILES
O=C(C(C=CC1=C23)=CC1=CC(Br)=C3C=CN=C2N)O
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
MK256 Related Classifications
HY-183423 Related Classifications
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