JAK1/TYK2-IN-3

JAK1/TYK2-IN-3 is a potent, selective and orally active dual TYK2/JAK1 inhibitor with IC50 values of 6 and 37 nM, respectively. JAK1/TYK2-IN-3 also shows selectively relative to JAK2 (IC50=140 nM) and JAK3 (IC50=362 nM). JAK1/TYK2-IN-3 shows anti-inflammatory effect by regulating the expression of related TYK2/JAK1-regulated genes, as well as the formation of Th1, Th2, and Th17 cells[1].

Signaling Pathways >> JAK/STAT Signaling >> JAK

Signaling Pathways >> Epigenetics >> JAK

Signaling Pathways >> Stem Cell/Wnt >> JAK

Research Areas >> Inflammation/Immunology

Tyk2:6 nM (IC50)

JAK1:37 nM (IC50)

JAK2:140 nM (IC50)

JAK3:362 nM (IC50)

JAK1/TYK2-IN-3 (compound 48) (10, 20, 30 mg/kg) shows anti-inflammatory effect by regulating the formation of Th1, Th2, Th17 cells[1]. JAK1/TYK2-IN-3 (10, 20, 30 mg/kg) inhibits the NF-κB signaling pathway by inhibits the JAK-STAT pathway, thereby reducing the inflammatory response in ulcerative colitis (UC) mice[1]. JAK1/TYK2-IN-3 (10, 20, 30 mg/kg) dose-dependently inhibits the mRNA expression of TNF-α, IL-1β, IL-12, IL-17A, IL-22, IFN-α, and IFN-β[1].

JAK1/TYK2-IN-3 (10, 20, 30 mg/kg; p.o.; twice a day for 12 days) shows a good therapeutic effect on ulcerative colitis (UC)[1]. JAK1/TYK2-IN-3 (5 mg/kg, p.o.) shows 23.7% oral bioavailability in rats[1]. Pharmacokinetic Parameters of JAK1/TYK2-IN-3 in male Sprague-Dawley rats[1]. compd dose(mg/kg) Administration Cmax(ng/mL) Cl (Lh-1kg-1) T1/2(h) AUC0-t(ng·h/mL) F (%) 48 5 mg/kg p.o. 400.4±55.3 11.3±5.2 2.4±2.1 440.9±157.0 23.7 Animal Model: 6-8 weeks, 270-325g male Sprague-Dawley rats[1] Dosage: 5 mg/kg Administration: p.o. Result: Showed 23.7% oral bioavailability in rats. Animal Model: Six-eight week old male C57BL/6 mice, 20-22 g (2.5% dextran sulfate sodium (DSS)-induced acute UC mouse model)[1] Dosage: 10, 20, 30 mg/kg Administration: p.o., twice a day, 12 days Result: Improved the infiltration of inflammatory factors and reduced the damage caused by DSS.

[1]. Yang T, et al. Identification of a Novel 2,8-Diazaspiro[4.5]decan-1-one Derivative as a Potent and Selective Dual TYK2/JAK1 Inhibitor for the Treatment of Inflammatory Bowel Disease. J Med Chem. 2022; 65(4):3151-3172.