JAK3 (Janus kinase 3) is a tyrosine kinase enzyme that in humans. Importantly, The JAK3 protein transmits chemical signals from outside the cell to the cell’s nucleus. Particularly, JAK3 protein regulates the growth and maturation of certain types of white blood cells (lymphocytes). Moreover, mutations that abrogate Jak3 functions cause an autosomal severe combined immunodeficiency disease (SCID). While activating Jak3 mutation leads to the development of hematologic and epithelial cancers.
TEC (Tyrosine-protein kinase Tec) is a tyrosine kinase that in humans is encoded by the TEC gene. In addition, Tec kinase plays an important role in T-cell activation. Moreover, Upon TCR/CD28 stimulation, Tec kinase takes part in a signaling pathway that leads to the activation of IL-2 and IL-4 cytokine promoters.
In this article, we will introduce a potent and oral JAK3/TEC dual inhibitor,Ritlecitinib.
Ritlecitinib (PF-06651600) is a potent and selective JAKS inhibitor with IC50s of >10000, >10000, 33.1, >10000 nM for JAK1, JAK2, JAK3, TYK2 respectively. Besides, Ritlecitinib 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. In addition, Ritlecitinib inhibits Th1 and Th17 T cell differentiation. Additionally, Ritlecitinib inhibits the phosphorylation of STAT3 elicited by IL-21 with an IC50 of 355 nM. Moreover, Ritlecitinib (0-100 µM) suppresses Th1 and Th17 function as measured by the inhibition of IFNγ production with IC50 values of 48, and 269 nM, respectively.
Ritlecitinib significantly reduces disease severity in the experimental autoimmune encephalomyelitis (EAE) mouse model when dosed either therapeutically at 30 or 100 mg/kg or prophylactically at 20 and 60 mg/kg. What’s more, Ritlecitinib has the potential for the research of alopecia areata.
All in all, Ritlecitinib is an orally active JAK3/TEC dual inhibitor for patchy hair loss research.