In vitro: PF-06651600, a newly discovered potent JAK3-selective inhibitor, is highly efficacious at inhibiting γc cytokine signaling, which is dependent on both JAK1 and JAK3. In vitro, it inhibits Th1 and Th17 cell differentiation and function. In total lymphocytes in human whole blood, PF-06651600 inhibits the phosphorylation of STAT5 elicited by IL-2, IL-4, IL-7, and IL-15 with IC50 values of 244, 340, 407, and 266 nM, respectively, and it inhibits the phosphorylation of STAT3 elicited by IL-21 with an IC50 of 355 nM.
In vivo: In vivo, PF-06651600 reduces disease pathology in rat adjuvant-induced arthritis as well as in mouse experimental autoimmune encephalomyelitis models. PF-06651600 has suitable pharmacokinetics and pharmacodynamics properties for preclinical and clinical evaluations. Human pharmacokinetics of PF-06651600 are predicted to show approximate values of blood clearance of 5.6 mL/min/kg, a steady state volume of distribution of 1.3 L/kg, oral bioavailability of 90%, and a systemic half-life of 2 h.
|Animal models||female Lewis rats (8 to 10 weeks old)|
|Formulation||2% Tween 80 /0.5% methylcellulose/deionized water|
|Dosages||80, 15, or 6 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||10 mM in DMSO|
Jak3 deficiency blocks innate lymphoid cell development.
Robinette ML, et al. Mucosal Immunol. 2018 Jan;11(1):50-60. PMID: 28513593.
Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition.
Telliez JB, et al. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451. PMID: 27791347.
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