| Size | Price | Stock | Qty |
|---|---|---|---|
| 10mg |
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| 1g | |||
| Other Sizes |
| Targets |
CDK
SEL120-34A is a selective ATP-competitive CDK8 inhibitor with IC50s of 4.4 nM and 10.4 nM for CDK8/CycC and CDK19/CycC, respectively. SEL120-34A has no clear inhibitory impact on CDK1, 2, 4, 6, 5, and 7, and only mildly inhibits CDK9 (IC50, 1070 nM). SEL120-34A is active against a panel of AML cell lines (GI50<1 μM) such as SKNO-1, KG-1, HEL-60, MOLM-16, MV-4-11, OciAML-2, MOLM-6 and OciAML -3 cells, similar with the effective inhibitory range of STAT1 S727 and STAT5 S726 [1]. |
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| ln Vitro |
SEL120-34A is a selective ATP-competitive CDK8 inhibitor with IC50s of 4.4 nM and 10.4 nM for CDK8/CycC and CDK19/CycC, respectively. SEL120-34A has no clear inhibitory impact on CDK1, 2, 4, 6, 5, and 7, and only mildly inhibits CDK9 (IC50, 1070 nM). SEL120-34A is active against a panel of AML cell lines (GI50<1 μM) such as SKNO-1, KG-1, HEL-60, MOLM-16, MV-4-11, OciAML-2, MOLM-6 and OciAML -3 cells, similar with the effective inhibitory range of STAT1 S727 and STAT5 S726 [1].
SEL120-34A inhibits STAT1 S727 and STAT5 S726 phosphorylation in a dose-dependent manner in HCT-116 and SET-2 cells upon IFNγ or IFNα stimulation.[1] It suppresses serum-induced expression of immediate early response genes (EGR1 and FOS) in HCT-116 cells.[1] In KG-1 AML cells, SEL120-34A inhibits STAT5 S726 phosphorylation within 1 hour, with sustained inhibition observed after washout, indicating long cellular residence time.[1] Prolonged treatment (up to 6 days) induces apoptosis, evidenced by cleaved Caspase-3.[1] SEL120-34A shows differential growth inhibition in AML cell lines: sensitive lines (KG-1, MV4-11, etc.) have high STAT5 S726/STAT1 S727 phosphorylation; resistant lines (MOLM-13, etc.) are negative for these marks.[1] |
| ln Vivo |
SEL120-34A (30, 60 mg/kg, orally) suppresses tumor growth in mice harboring MV4-11 cancer cells. It also inhibits the growth of tumors produced from KG-1 when administered at a dose of 30 mg/kg [1].
Oral administration of SEL120-34A inhibits tumor growth in KG-1 and MV4-11 AML xenograft models in SCID mice, without significant body weight loss.[1] In Colo-205 CRC xenografts, it reduces phosphorylation of STAT1 S727 and STAT5 S726 in a dose-dependent manner.[1] Transcriptomic analysis of treated tumors shows downregulation of IFN-responsive and STAT-regulated genes (e.g., IRF9, ISG15, STAT1).[1] |
| Enzyme Assay |
Kinase activity of CDK8/CycC and CDK19/CycC was measured using a radiometric protein kinase assay. Dose-response curves were constructed to determine IC₅₀ values at Km ATP concentrations.[1]
A Eu kinase binding assay was used to measure binding affinity (Kd) of SEL120-34A to CDK8.[1] Kinase capture experiments using ATP-desthiobiotin probes in KG-1 cell lysates confirmed dose-dependent competitive binding to CDK8.[1] |
| Cell Assay |
Cells were treated with SEL120-34A or vehicle, followed by IFN or serum stimulation. Phosphorylation levels of STAT1 S727, STAT5 S726, and other targets were assessed by Western blot.[1]
For gene expression studies, cells were synchronized in low serum, pretreated with compound, stimulated, and RNA was extracted for qRT-PCR.[1] Extended cytotoxicity assays were performed in AML cell lines using AlamarBlue, with GI₅₀ values calculated from dose-response curves over 10 days.[1] |
| Animal Protocol |
SCID mice were inoculated subcutaneously with AML (KG-1, MV4-11) or CRC (Colo-205) cells. Once tumors reached ~100–250 mm³, mice were randomized and treated orally with SEL120-34A dissolved in water, administered once daily or BID.[1]
Tumor volumes and body weights were monitored. At endpoints, tumors and blood were collected for pharmacodynamic and pharmacokinetic analyses.[1] A 14-day toxicology study in CD-1 mice involved daily oral dosing, with hematological parameters assessed at study end.[1] |
| ADME/Pharmacokinetics |
After oral administration of 60 mg/kg of SEL120-34A to mice, the plasma concentration at 16 hours was >700 ng/mL. [1]
This compound showed good bioavailability and metabolic stability, and can be used for in vivo efficacy studies. [1] |
| Toxicity/Toxicokinetics |
In a 14-day subchronic toxicity study in CD-1 mice, SEL120-34A did not cause significant changes in hematological parameters or body weight. [1]
|
| References |
[1]. SEL120-34A is a novel CDK8 inhibitor active in AML cells with high levels of serine phosphorylation of STAT1 and STAT5 transactivation domains. Oncotarget. 2017 May 16;8(20):33779-33795.
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| Additional Infomation |
RVU120, a CDK8/19 inhibitor, is an orally bioavailable cyclin-dependent kinase 8 and 19 (CDK8/19) inhibitor with potential antitumor and chemoprotective activities. After oral administration, RVU120 targets and inhibits CDK8/19 activity, thereby preventing the activation of CDK8/19-mediated oncogenic signaling pathways, blocking the selective transcription of various pro-tumorigenic genes, and inhibiting the proliferation of CDK8/19-overexpressing tumor cells. CDK8/19 are serine/threonine kinases involved in cell cycle regulation, overexpressed in certain cancer cell types, and play a crucial role in tumor cell proliferation. SEL120-34A is a tricyclic benzimidazole-based type I CDK8 inhibitor that binds to the ATP-binding pocket and forms a halogen bond with the hinge region. [1]
It selectively inhibits serine phosphorylation of STAT1/5 without affecting tyrosine phosphorylation or CDK9-mediated RNAPII phosphorylation. [1] Transcriptome analysis suggests that its effects are primarily focused on IFN-responsive genes and NUP98-HOXA9-regulated genes, suggesting a potential role in targeting leukemia stem cell-like cells. [1] It is considered a candidate drug for personalized treatment of STAT5 S726 hyperphosphorylated AML. [1] |
| Molecular Formula |
C15H18BR2N4
|
|---|---|
| Molecular Weight |
414.14
|
| Exact Mass |
449.964
|
| CAS # |
1609522-33-9
|
| Related CAS # |
SEL120-34A monohydrochloride;2443816-41-7;SEL120-34A HCl;1609452-30-3
|
| PubChem CID |
73776232
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| Appearance |
Typically exists as solid at room temperature
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
3
|
| Rotatable Bond Count |
1
|
| Heavy Atom Count |
22
|
| Complexity |
390
|
| Defined Atom Stereocenter Count |
0
|
| InChi Key |
GQXLWUCQESKBSC-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C15H18Br2N4.ClH/c1-9-11(16)12(17)10-3-2-6-21-14(10)13(9)19-15(21)20-7-4-18-5-8-20;/h18H,2-8H2,1H3;1H
|
| Chemical Name |
6,7-dibromo-5-methyl-2-piperazin-1-yl-1,3-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene;hydrochloride
|
| Synonyms |
1609522-33-9; UNII-6LGR0RYY5Q; SEL120-34A free base; CDK8-IN-2 free base; 6LGR0RYY5Q; 4H-Imidazo(4,5,1-ij)quinoline, 7,8-dibromo-5,6-dihydro-9-methyl-2-(1-piperazinyl)-; 7,8-DIBROMO-5,6-DIHYDRO-9-METHYL-2-(1-PIPERAZINYL)-4H-IMIDAZO(4,5,1-IJ)QUINOLINE; RefChem:182254;
|
| 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 |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4146 mL | 12.0732 mL | 24.1464 mL | |
| 5 mM | 0.4829 mL | 2.4146 mL | 4.8293 mL | |
| 10 mM | 0.2415 mL | 1.2073 mL | 2.4146 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.
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