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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- CAS No.: 2271348-04-8
- Formule: C14H9BrN2O2
- Masse moléculaire:317.14
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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Chemical Information
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- Pureté et documentation
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Help & FAQs
Activité biologique
Description
IC50 & Target
[1]|
CDK8/cyclin C 2.5 nM (IC50) |
CDK19/CycC 3.3 nM (IC50) |
STAT1 |
STAT5 |
Mcl-1 |
In Vitro
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. Further protocols information, click here.
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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.
Parmacokinetics
In Vivo
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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CAS No. 2271348-04-8
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Masse moléculaire 317.14
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Formule C14H9BrN2O2
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SMILES
O=C(C(C=CC1=C23)=CC1=CC(Br)=C3C=CN=C2N)O
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Protocole
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RNA extraction experimental
By lysing cells, releasing RNA, and removing impurities such as proteins and DNA, high-purity RNA products are finally obtained. The commonly used traditional method is the guanidine isothiocyanate/phenol/chloroform method (Trizol), which is suitable for a variety of animal materials including animal tissues, microorganisms, cultured cells, etc., and most plant materials.
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Cell Cytotoxicity Assay
Cytotoxicity assays are usually based on the assessment of cell membrane damage, which can also be indirectly detected by measuring cell viability. Detection methods include MTT assay, CKK-8 assay, LDH assay and ATP assay, etc.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
MK256 Related Classifications
HY-183423 Related Classifications
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