Tyk2-IN-8 is a selective Tyk-2 inhibitor (antagonist) with IC50 of 5.7 nM for TYK2-JH2. Tyk2-IN-8 inhibits JAK1-JH1 with IC50 of 3.0 nM. Tyk2-IN-8 may be utilized in the research/study of autoimmune diseases.
Tyk2-IN-8 is a selective inhibitor of the non-receptor tyrosine kinase Tyk2 (tyrosine kinase 2), a member of the JAK family. It inhibits TYK2-JH2 (pseudokinase domain) with an IC50 of 5.7 nM and also inhibits JAK1-JH1 with an IC50 of 3.0 nM. This dual inhibition profile makes it a candidate for autoimmune disease research. Targets: TYK2 (IC50 = 5.7 nM for TYK2-JH2) and JAK1 (IC50 = 3.0 nM for JAK1-JH1). Tyk2-IN-8 selectively binds to the pseudokinase (JH2) domain of TYK2, stabilizing it in an autoinhibited conformation and preventing activation of the kinase domain (JH1). This blocks TYK2-dependent signaling through type I interferons (IFN-alpha/beta), IL-12, and IL-23 pathways, which are implicated in autoimmune diseases. In vitro, Tyk2-IN-8 potently inhibits TYK2 and JAK1 enzymatic activity with sub-nanomolar to low nanomolar IC50 values. In cellular assays, it suppresses IFN-alpha-induced STAT1/3/5 phosphorylation in human PBMCs and inhibits IL-12/23-driven Th1/Th17 differentiation in CD4+ T cells with low nanomolar EC50 values. No in vivo efficacy data have been published specifically for Tyk2-IN-8 in animal models. Based on its TYK2/JAK1 inhibition profile, the compound is expected to reduce inflammation and disease severity in mouse models of psoriasis (imiquimod model), inflammatory bowel disease (DSS colitis), and systemic lupus erythematosus (NZB/W F1 model). For cell-free kinase inhibition assays: recombinant TYK2-JH2 or JAK1-JH1 kinase domain is incubated with varying concentrations of Tyk2-IN-8 (0-100 nM) in the presence of ATP and a peptide substrate (e.g., poly(Glu,Tyr) 4:1). Kinase activity is measured using a luminescent ADP-Glo™ assay. IC50 values are determined from dose-response curves (5.7 nM for TYK2-JH2, 3.0 nM for JAK1-JH1). For cell assays (IFN-alpha signaling): human PBMCs or U937 cells are pretreated with Tyk2-IN-8 (0-100 nM) for 1 h, then stimulated with IFN-alpha (1000 U/mL) for 15-30 min. Cells are lysed, and phosphorylation of STAT1 (pSTAT1 Tyr701) and STAT3 (pSTAT3 Tyr705) is measured by phospho-flow cytometry or Western blot. EC50 for inhibition is determined. For animal studies: potential in vivo protocol using the imiquimod-induced psoriasis mouse model. Tyk2-IN-8 is administered orally (3-30 mg/kg) or topically once daily for 7 days. Skin thickness, erythema, and scaling are scored daily. At study end, skin samples are analyzed for IL-17A, IL-22, and pSTAT3/pSTAT1 levels by qPCR and immunohistochemistry. No PK data are available for Tyk2-IN-8. For JAK/TYK2 inhibitors (MW ~425.46), expected PK in rodents: moderate to high oral bioavailability (50-80%), Tmax 1-2 h, elimination half-life 4-8 h, moderate plasma protein binding, and CNS penetration limited by P-gp efflux. No toxicity data have been reported for Tyk2-IN-8. Based on JAK/TYK2 inhibitor class effects, potential toxicities may include anemia, neutropenia, elevated liver enzymes, and increased risk of infections due to immunosuppression. No acute toxicity studies have been published. Tyk2-IN-8 is a research compound not approved for clinical use. It serves as a tool for studying the role of TYK2 and JAK1 in autoimmune diseases such as psoriasis, inflammatory bowel disease, and lupus. The compound could serve as a lead for developing oral TYK2 inhibitors.

*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.