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| Targets |
TyK2-IN-2 targets TYK2 (tyrosine kinase 2), a member of the Janus kinase (JAK) family that plays a critical role in cytokine signaling through the JAK-STAT pathway. It is a potent and selective TYK2 inhibitor with an IC₅0 of 7 nM for the TYK2 JH2 domain. By inhibiting TYK2, the compound blocks the signaling of pro-inflammatory cytokines such as IL-23 and IFNalpha. TyK2-IN-2 also inhibits PDE4 with an IC₅0 of 62 nM, providing additional anti-inflammatory effects.
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| ln Vitro |
TyK2-IN-2 (compound 18) bound to TYK2 JH2 has its cocrystal structure solved. The first thing that is evident is the restricted space between C8 and the hinge, which is in line with the loss of affinity noted for groups that are bigger than the methylamino group at this particular location. Hydrogen bonds are also present between the N1 of the IZP core and the "hinge" and the NH of the C8 methylamine (Val690). More hydrogen bonds were seen forming between Lys642 and the oxygen of the C3 amide, as well as between Glu688's hinge carbonyl and the bridging water molecule. A small residue (Ala671) under the "gatekeeper" (Thr687) and the highly kinase conserved substitution DPG are among the residues that make up the pocket near the C3 amide of the TYK2 JH2 domain that are largely unique in relation to the kinome. The DFG motif also changes the localization of the conserved catalytic Lys642 and Asp759. The primary source of kinome selectivity for TyK2-IN-2 (compound 18) is assumed to be the C3 amide's capacity to collaborate and bind to this pocket [1].
In vitro, TyK2-IN-2 is a potent and selective TYK2 inhibitor with IC₅0 values of 7 nM for TYK2 JH2, 0.1 microM for IL-23, and 0.05 microM for IFNalpha. It also inhibits PDE4 with an IC₅0 of 62 nM. By inhibiting TYK2 and PDE4, the compound modulates immune responses and has potential applications in inflammatory and autoimmune diseases. Its dual inhibitory mechanism makes it a valuable tool for studying inflammatory signaling pathways. |
| ln Vivo |
In vivo studies of TyK2-IN-2 are focused on evaluating its efficacy in animal models of inflammatory and autoimmune diseases. As a potent TYK2 inhibitor with additional PDE4 inhibitory activity, the compound is expected to demonstrate significant anti-inflammatory effects in vivo. Further in vivo studies are needed to fully characterize its efficacy, safety, and pharmacokinetic profile.
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| Enzyme Assay |
For in vitro enzyme/receptor binding assays, TyK2-IN-2 can be evaluated using kinase activity assays that measure TYK2-mediated phosphorylation. The compound is incubated with recombinant TYK2 kinase and ATP at various concentrations. Kinase activity is quantified by measuring phosphorylation of peptide substrates using radiometric, fluorescence-based, or ELISA methods. IC₅0 values are determined from dose-response curves. PDE4 inhibitory activity is assessed using similar enzymatic assays. Selectivity profiling against other kinases and PDE isoforms may be performed.
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| Cell Assay |
For in vitro cellular experiments, TyK2-IN-2 is tested in cell lines or primary cells to evaluate its effects on cytokine signaling and immune function. Cells are cultured in appropriate media and treated with various concentrations of the compound. TYK2-mediated signaling is assessed by measuring STAT phosphorylation using Western blotting. Cytokine production and immune cell activation are measured using ELISA or flow cytometry. The compound's effects on PDE4 activity can also be assessed by measuring cAMP levels.
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| Animal Protocol |
For in vivo animal experiments, TyK2-IN-2 can be administered to rodents via various routes, including oral gavage, intravenous injection, or intraperitoneal injection. The compound's efficacy can be evaluated in models of inflammatory and autoimmune diseases, such as psoriasis, rheumatoid arthritis, or inflammatory bowel disease. Typical dosing regimens may range from 1 to 50 mg/kg. Inflammatory markers, disease severity, and immune cell infiltration are assessed.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of TyK2-IN-2 are not extensively detailed in the provided references. As a small molecule with a molecular weight of 310.35, it may have reasonable oral bioavailability and tissue distribution. The compound is soluble in DMSO at ≥20 mg/mL. Detailed parameters such as Cₘₐₓ, Tₘₐₓ, AUC, half-life, and clearance would need to be determined through comprehensive PK studies.
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| Toxicity/Toxicokinetics |
Toxicological data for TyK2-IN-2 are limited, as it is primarily a research tool. As a TYK2 and PDE4 inhibitor, its toxicity would depend on the importance of these targets for normal immune function and physiology. Comprehensive toxicology studies including acute and repeated-dose toxicity, genotoxicity, and cardiotoxicity assessments would be needed for further development. Appropriate safety precautions should be taken when handling this compound.
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| References | |
| Additional Infomation |
TyK2-IN-2 is a research compound used to study TYK2 and PDE4 biology and develop therapies for inflammatory and autoimmune diseases. No clinical trials or regulatory approvals have been reported for this compound as a therapeutic agent. It is available from various chemical suppliers for research purposes only. The compound is a potent and selective TYK2 inhibitor with IC₅0 values of 7 nM, 0.1 microM, and 0.05 microM for TYK2 JH2, IL-23, and IFNalpha, respectively.
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| Molecular Formula |
C16H18N6O
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| Molecular Weight |
310.35372209549
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| Exact Mass |
310.154
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| CAS # |
2098466-94-3
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| PubChem CID |
129626433
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| Appearance |
White to off-white solid powder
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| LogP |
2.1
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
23
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| Complexity |
423
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CNC1=CC(NC2=CC(C)=CC(C)=C2)=NN3C1=NC=C3C(N)=O
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| InChi Key |
SNVFFECYFQEWTL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H18N6O/c1-9-4-10(2)6-11(5-9)20-14-7-12(18-3)16-19-8-13(15(17)23)22(16)21-14/h4-8,18H,1-3H3,(H2,17,23)(H,20,21)
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| Chemical Name |
6-(3,5-dimethylanilino)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide
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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 |
| 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 : ≥ 25 mg/mL (~80.55 mM)
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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 | 3.2222 mL | 16.1108 mL | 32.2217 mL | |
| 5 mM | 0.6444 mL | 3.2222 mL | 6.4443 mL | |
| 10 mM | 0.3222 mL | 1.6111 mL | 3.2222 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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