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| Other Sizes |
| Targets |
CDK8 0.61 nM (IC50); CDK19 4.28 nM (IC50); GSK3α 76.67 nM (IC50); GSK3β 63.06 nM (IC50); STAT5
AS2863619 targets cyclin-dependent kinases 8 and 19 (CDK8 and CDK19). The compound inhibits CDK8 with an IC50 of 0.61 nM and CDK19 with an IC50 of 4.28 nM. CDK8 and CDK19 are components of the Mediator complex, which regulates RNA polymerase II-dependent transcription. By inhibiting CDK8/19, AS2863619 modulates gene expression programs that are dependent on Mediator complex function. One of the key effects of CDK8/19 inhibition is the induction of Foxp3 expression in Tconv cells, which promotes their differentiation into Tregs. The compound is a potent Foxp3 inducer with an EC50 of 32.5 nM. |
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| ln Vitro |
Treatment with AS2863619 (1 μM; 22 hours; mouse CD4+ T cells) reduces serine phosphorylation of STAT5b's PSP motif to around 40% while increasing tyrosine phosphorylation in the C-terminal domain to approximately 160% of control-treated samples[1].
AS2863619 has demonstrated potent in vitro activity as a CDK8/19 inhibitor and Foxp3 inducer. The compound inhibits CDK8 with an IC50 of 0.61 nM and CDK19 with an IC50 of 4.28 nM. In Tconv cells, AS2863619 induces Foxp3 expression with an EC50 of 32.5 nM. The induction of Foxp3 leads to the transdifferentiation of Tconv cells into Tregs, which are characterized by their immunosuppressive function and expression of Treg markers such as CD25 and CTLA-4. The compound’s ability to induce Tregs makes it a promising tool for studying immune regulation and for developing therapies for autoimmune diseases and transplantation. |
| ln Vivo |
After sensitization to 2,4-dinitrofluorobenzene (DNFB), mice treated with AS2863619 (30 mg/kg; oral administration; daily; for 2 weeks) showed reduced levels of secondary response, milder infiltration of inflammatory cells into the skin, and lower ratios of interferon-γ+ (IFN-γ+) cells in a skin contact hypersensitivity model when compared to vehicle-treated control mice. AS2863619-induced suppression is eliminated by treg depletion prior to the subsequent reaction being elicited. Mice treated with AS2863619 and sensitized to DNFB exhibit a particular increase in KLRG1+ Foxp3+ T cells[1].
AS2863619 has been evaluated in animal models. Oral administration of AS2863619 in a SARS-CoV-2 infected mouse model did not markedly improve early weight loss, gross lung inflammatory scores, bronchoalveolar lavage fluid (BALF) viral RNA levels, or histopathological findings. However, the compound’s ability to induce Tregs suggests that it could have therapeutic applications in other disease models where immune regulation is beneficial. Further studies would be needed to evaluate the efficacy of AS2863619 in autoimmune disease models or transplantation models. |
| Enzyme Assay |
The kinase inhibitory activity of AS2863619 can be assessed using in vitro kinase assays. In a typical assay, recombinant CDK8 or CDK19 kinase is incubated with a peptide substrate, ATP, and varying concentrations of AS2863619. The incorporation of phosphate into the substrate is measured, and the half-maximal inhibitory concentration (IC50) is calculated from dose-response curves. The IC50 for CDK8 inhibition is 0.61 nM, and the IC50 for CDK19 inhibition is 4.28 nM. The selectivity of AS2863619 against a panel of other kinases can be assessed using kinase profiling services to determine its off-target effects.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: Mouse CD4+ T cells Tested Concentrations: 1 μM Incubation Duration: 22 hrs (hours) Experimental Results: Suppressed serine phosphorylation of the PSP motif of STAT5b to ~40% while enhancing tyrosine phosphorylation in the C-terminal domain to ~160% of control-treated samples. The cellular activity of AS2863619 is assessed using primary Tconv cells or T cell lines. Cells are treated with AS2863619 at varying concentrations in the presence of TGF-β1 and IL-2, which are required for Treg differentiation. Foxp3 expression is assessed by flow cytometry using intracellular staining with anti-Foxp3 antibodies. The induction of other Treg markers, such as CD25 and CTLA-4, is also assessed by flow cytometry. The suppressive function of the induced Tregs is assessed by co-culture assays with effector T cells. |
| Animal Protocol |
Animal/Disease Models: Mice with DNFB-induced contact skin hypersensitivity[1]
Doses: 30 mg/kg Route of Administration: Oral administration; daily; for 2 weeks Experimental Results: The degree of the secondary response, with milder infiltration of inflammatory cells into the skin and diminished ratios of interferon-γ+ (IFN-γ+) cells. AS2863619 has been evaluated in a SARS-CoV-2 infected mouse model. Mice were infected with SARS-CoV-2 and treated with AS2863619 by oral administration. The effects of the compound on weight loss, lung inflammation, viral RNA levels, and histopathological findings were assessed. The compound did not markedly improve these parameters in this model. Future studies may involve the use of autoimmune disease models, such as experimental autoimmune encephalomyelitis (EAE) or colitis models, to assess the efficacy of AS2863619 in inducing Tregs and suppressing inflammation. |
| ADME/Pharmacokinetics |
AS2863619 is described as orally bioavailable, suggesting that it has favorable pharmacokinetic properties. The compound is a small molecule that can be administered orally. Further studies would be needed to characterize the absorption, distribution, metabolism, and excretion (ADME) properties of AS2863619, including plasma protein binding, clearance, half-life, and tissue distribution.
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| Toxicity/Toxicokinetics |
No detailed toxicity data for AS2863619 has been published in the available literature. As a research compound, AS2863619 has not been subjected to comprehensive toxicology studies. The mechanism of action, which involves the inhibition of CDK8/19 and the induction of Tregs, could have off-target effects on the immune system or on other cellular processes that depend on Mediator complex function. Further studies would be needed to assess the safety profile of AS2863619.
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| References | |
| Additional Infomation |
AS2863619 is a potent, selective, and orally bioavailable inhibitor of CDK8 and CDK19, with IC50 values of 0.61 nM and 4.28 nM, respectively. The compound is a potent Foxp3 inducer in Tconv cells, with an EC50 of 32.5 nM, promoting their transdifferentiation into Tregs. AS2863619 has potential therapeutic applications for autoimmune diseases, transplantation, and other conditions where immune regulation is beneficial. The compound is a valuable research tool for studying the role of CDK8/19 in transcription and immune regulation.
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| Molecular Formula |
C16H14CL2N8O
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|---|---|
| Molecular Weight |
405.2414
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| Exact Mass |
404.066
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| CAS # |
2241300-51-4
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| Related CAS # |
AS2863619 free base;2241300-50-3
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| PubChem CID |
139600293
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
27
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| Complexity |
495
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O1N=C(C(C2=NC3C=NC=CC=3N2C2C=CC3=C(C=2)NC(C)=N3)=N1)N.Cl.Cl
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| InChi Key |
LHUAALWRORLTCJ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H12N8O.2ClH/c1-8-19-10-3-2-9(6-11(10)20-8)24-13-4-5-18-7-12(13)21-16(24)14-15(17)23-25-22-14;;/h2-7H,1H3,(H2,17,23)(H,19,20);2*1H
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| Chemical Name |
4-[1-(2-methyl-3H-benzimidazol-5-yl)imidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine;dihydrochloride
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| Synonyms |
AS2863619; AS-2863619; 2241300-51-4; AS 2863619; 4-(1-(2-Methyl-1H-benzo[d]imidazol-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine dihydrochloride; 4-[1-(2-methyl-1H-benzimidazol-6-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine, dihydrochloride; 4-[1-(2-Methyl-3H-benzimidazol-5-yl)imidazo[4,5-c]pyridin-2-yl]-1,2,5-oxadiazol-3-amine;dihydrochloride; .
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| 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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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) |
DMSO : 250 mg/mL (616.9 mM)
H2O : ≥ 100 mg/mL (246.77 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.62 mg/mL (6.47 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.62 mg/mL (6.47 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.25 mg/mL (5.55 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.25 mg/mL (5.55 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 22.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 5: ≥ 2.25 mg/mL (5.55 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 22.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4677 mL | 12.3384 mL | 24.6767 mL | |
| 5 mM | 0.4935 mL | 2.4677 mL | 4.9353 mL | |
| 10 mM | 0.2468 mL | 1.2338 mL | 2.4677 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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