In vitro: Ritlecitinib (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, Ritlecitinib (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.
FOUNDRY JOURNAL. 2023 Sep.
A REVOLUTIONARY DRUG: RITLECITINIB
Ritlecitinib (PF-06651600) purchased from AbMole
| Cell Experiment | |
|---|---|
| Cell lines | Th1 and Th17 cells |
| Preparation method | T-cell differentiation in Th1 or Th17 is dependent on cytokines some of which being JAK3-dependent like IL-2 for Th1 cells and IL-21 for Th17 cells, and some being JAK3-independent such as IL-6 and IL-23 for Th17 cells. We therefore assessed the effect of JAK3-versus JAK1-selective inhibition on T helper differentiation. Functional assessment in T-cell differentiation assays demonstrated that PF-06651600 suppressed Th1 and Th17 differentiation as measured by IFNγ, after 5 days under Th1 conditions, and IL-17 production, after 6 days under Th17 conditions, with IC50 values of 30 nM and 167 nM, respectively (Figures 2A and B). PF-06651600 also suppressed Th1 and Th17 function as measured by the inhibition of IFNγ production (IC50 = 48 nM) (Figure 2C) and IL-17 production (IC50 = 269 nM) (Figure 2D) in cells that had been previously differentiated, and rested before being treated with PF-06651600. |
| Concentrations | - |
| Incubation time | 2 days |
| Animal Experiment | |
|---|---|
| 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 |
| Administration | oral gavage |
| Molecular Weight | 285.34 |
| Formula | C15H19N5O |
| CAS Number | 1792180-81-4 |
| Solubility (25°C) | DMSO ≥ 60 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
[1] Robinette ML, et al. Mucosal Immunol. Jak3 deficiency blocks innate lymphoid cell development.
| Related JAK Products |
|---|
| A-005
A-005 is a potentially first-in-class, brain-penetrating TYK2 allosteric inhibitor for studies related to neuroinflammatory and neurodegenerative diseases. |
| Tyrosine Protein Kinase JAK 2 (Phospho-Tyr8, 9)
Tyrosine Protein Kinase JAK 2 (Phospho-Tyr8, 9) is a peptide corresponding to amino acids 475 to 491 of mouse JAK2. |
| JAK2/FLT3-IN-1 TFA
JAK2/FLT3-IN-1 (TFA) is a potent and orally active dual JAK2/FLT3 inhibitor with IC50 values of 0.7 nM, 4 nM, 26 nM and 39 nM for JAK2, FLT3, JAK1 and JAK3, respectively. |
| ZT55
ZT55 is an orally active and highly-selective JAK2 inhibitor with an IC50 value of 0.031 μM. |
| ZM39923
ZM39923 is a JAK3 inhibitor, with a pIC50 of 7.1; ZM39923 also potently inhibits tissue transglutaminase (TGM2) with an IC50 of 10 nM. |
Products are for research use only. Not for human use. We do not sell to patients.
© Copyright 2010-2023 AbMole BioScience. All Rights Reserved.
