JAK2/TYK2-IN-1

JAK2/TYK2-IN-2 is a potent and selective TYK2 inhibitor with IC50 values of 9 and 157 nM for TYK2 and JAK2, respectively. JAK2/TYK2-IN-2 has anti-inflammatory activity[1].

Signaling Pathways >> JAK/STAT Signaling >> JAK

Signaling Pathways >> Epigenetics >> JAK

Signaling Pathways >> Stem Cell/Wnt >> JAK

Research Areas >> Inflammation/Immunology

Tyk2:9 nM (IC50)

JAK2:157 nM (IC50)

JAK2/TYK2-IN-2 (compound 14l; 0-10000 nM) inhibits the phosphorylation of STAT in vitro[1]. Western Blot Analysis[1] Cell Line: TF-1, H9, TF-1, THP-1 cells Concentration: 0-10000 nM Incubation Time: Result: After stimulation with IL-6 and IFN-α at a concentration of 100 to 5000 nM, JAK2/TYK2-IN-2 reduced JAK1/JAK2/TYK2 and JAK1/TYK2-dependent signal transduction in a dose-dependent manner and remarkably reduced IFN-α-induced phosphorylation at 10 000 nM.

JAK2/TYK2-IN-2 (10 and 20 mg/kg; oral administration; twice a day for 6 consecutive days) exhibits anti-inflammatory activity in a dose-dependent manner[1]. JAK2/TYK2-IN-2 (5, 20 mg/kg; oral administration; twice a day for 12 days) leads to a low oral bioavailability[1].Pharmacokinetic Parameters of JAK1/TYK2-IN-2 in Male Sprague-Dawley rats[1] PK parameters iv PK parameters p.o. AUC(0-t) (μg/L*h) 29.00 AUC(0-t) (μg/L*h) 13.89 MRT(0-t) (h) 4.98 MRT(0-t) (h) 2.76 t1/2 (h) 5.95 t1/2 (h) 3.64 Cl (L/min/kg) 1.58 Cl (L/min/kg) 20.55 Vss (L/kg) 985.41 Vss (L/kg) 6564.28 Cmax (μg/L) 48.55 Cmax (μg/L) 8.00 Tmax (h) 1.00 F 11.96% Animal Model: Six-eight week old male C57BL/6 mice, 20-22 g (acute mice colitis model)[1] Dosage: 10, 20 mg/kg (dissolved in 5% EtOH, 1% Propylene glycol, 0.5% Tween 80 and 92.5% physiological saline) Administration: Oral administration, twice a day 6 consecutive days Result: Exhibited anti-inflammatory activity and have a good therapeutic effect on inflammatory bowel disease (IBD) in a dose-dependent manner.

[1]. Zhang C, et al. Discovery of 3-(4-(2-((1H-Indol-5-yl) amino)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl) propanenitrile Derivatives as Selective TYK2 Inhibitors for the Treatment of Inflammatory Bowel Disease. J Med Chem. 2021; 64(4):1966-1988.