Ritlecitinib (PF-06651600) is a potent and irreversible JAK3-selective inhibitor with an IC50 of 33.1 nM but without activity (IC50 > 10 000 nM) against JAK1, JAK2, and TYK2.
Storage Temp
Store at -20°C
Shipped In
Ice chest + Ice pads
Grade
Moligand™
Action Type
INHIBITOR
Mechanism of action
TEC family kinase inhibitor
Product Description
Information
Ritlecitinib (PF-06651600) is a potent and irreversibleJAK3-selectiveinhibitor with an IC50 of 33.1 nM but without activity (IC50 > 10 000 nM) against JAK1, JAK2, and TYK2.
Targets
JAK3 (Cell-free assay) 33.1 nM
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. 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
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.
1.Thorarensen A, Dowty ME, Banker ME, Juba B, Jussif J, Lin T, Vincent F, Czerwinski RM, Casimiro-Garcia A, Unwalla R et al.. (2017) Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans.. J Med Chem, 60 (5):(1971-1993). [PMID:28139931][10.1021/op500134e]
2.Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y et al.. (2016) Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition.. ACS Chem Biol, 11 (12):(3442-3451). [PMID:27791347][10.1021/op500134e]
3.King B, Guttman-Yassky E, Peeva E, Banerjee A, Sinclair R, Pavel AB, Zhu L, Cox LA, Craiglow B, Chen L et al.. (2021) A phase 2a randomized, placebo-controlled study to evaluate the efficacy and safety of the oral Janus kinase inhibitors ritlecitinib and brepocitinib in alopecia areata: 24-week results.. J Am Acad Dermatol, 85 (2):(379-387). [PMID:33757798][10.1021/op500134e]
4.Robinson MF, Damjanov N, Stamenkovic B, Radunovic G, Kivitz A, Cox L, Manukyan Z, Banfield C, Saunders M, Chandra D et al.. (2020) Efficacy and Safety of PF-06651600 (Ritlecitinib), a Novel JAK3/TEC Inhibitor, in Patients With Moderate-to-Severe Rheumatoid Arthritis and an Inadequate Response to Methotrexate.. Arthritis Rheumatol, 72 (10):(1621-1631). [PMID:32419304][10.1021/op500134e]
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