SAR-20347 is an inhibitor of TYK2, JAK1/2/3 (IC50: 0.6/23/26/41 nM).

JAK2:26nM, JAK1:23nM, TYK2:0.6 nM, JAK3:41 nM

SAR-20347 在NK-92细胞受IL-12刺激时，有效抑制IL-12介导的STAT4磷酸化（TYK2依赖性，IC50：126 nM）。SAR-20347（最大效应：5 μM）剂量依赖性地抑制分泌型胚胎碱性磷酸酶（SEAP）的产生。

与对照组动物相比，SAR-20347（60 mg/kg）能够在体内抑制TYK2信号传导，表现为抑制血清中IFN-γ的产量达91%。此外，通过平均信号强度的测量，SAR-20347显著减少了IL-17的产生，这与基因表达分析的结果是一致的。

Kinases are prepared in Base Reaction Buffer (20 mM Hepes pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/mL BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO) and substrate is added with 1.5 mM CaCl2, 16 μg/mL Calmodulin, and 2 mM MnCl2. Varying concentrations of SAR-20347 in DMSO are added to the kinase reaction along with 10 μM 33P-ATP (activity 0.01 μCi/μL final) for IC50 determination[1].

Cells are plated in a 96-well v-bottom plate in starvation medium, incubated with SAR-20347 (0.5% DMSO) for 20 minutes at 37°C, 5% CO2, and stimulated with individual cytokines. P-STAT levels are measured in duplicate using MSD plates following the manufacturer's instructions (MSD)[1].

Female 7 to 9-week old C57BL/6 mice are used. Mice are administered vehicle or 50 mg/kg SAR-20347 by oral gavage 30 minutes prior to application of 62.5 mg 5% imiquimod cream or control cream. Another dose of vehicle or 50 mg/kg SAR-20347 is given 5.5 hours following the first dose. This treatment is repeated for 5 days and on day 3 and 4, animals are injected with 100 uL saline to prevent dehydration. On the 6th day, the animals are euthanized and photographs are taken[1].