Ritlecitinib (malonate)

Ritlecitinib (PF-06651600) malonate is a highly selective, orally active, irreversible covalent JAK3 inhibitor (IC₅₀=33 nM) without inhibitory activity towards JAK1, JAK2, and TYK2 (IC₅₀ >10 μ M). Ritlecitinib malonate rapidly inactivates the JAK3 kinase, and blocks signaling and downstream STAT phosphorylation mediated by common gamma chain cytokines such as IL-2 and IL-15. Ritlecitinib malonate can inhibit Th1/Th17 cell differentiation and function, and effectively suppress preclinical animal models such as alopecia areata, adjuvant-induced arthritis (AIA), and experimental autoimmune encephalomyelitis (EAE)^[1][2][3]. In Vitro:Ritlecitinib malonate inhibits IL-15 in peripheral blood mononuclear cells (PBMCs) and heparin treated human whole blood (HWB) with IC₅₀ of 51 nM and 197 nM, respectively^[1].
Ritlecitinib malonate inhibits the phosphorylation of STAT proteins mediated by IL-2 (STAT5), IL-4 (STAT6), IL-7 (STAT5), IL-15 (STAT5), and IL-21 (STAT3) at concentrations of 244 nM, 340 nM, 407 nM, 266 nM, and 355 nM (IC₅₀), respectively^[2].
Ritlecitinib malonate (30 nM, 167 nM; 5 days, 6 days) inhibits cell differentiation in Th1 and Th17 cell differentiation inhibition experiments for 5 days under Th1 conditions and 6 days under Th17 conditions, respectively^[2].
In Vivo:Ritlecitinib (3, 10, 30 mg/kg; oral; once daily; 7 days) malonate reduces joint swelling and improves disease severity in a dose-dependent manner in the Sprague-Dawley rat adjuvant-induced arthritis (AIA) model^[2].
Ritlecitinib (30, 100 mg/kg (reversal); 20, 60 mg/kg (prevention); oral; once daily) malonate reduces disease severity in the mouse experimental autoimmune encephalomyelitis (EAE) model^[2].
Ritlecitinib (30 mg/kg; oral; once daily; 4 weeks) malonate can prevent the occurrence of alopecia areata in the C3H/HeJ mouse skin transplantation alopecia areata prevention model; Ritlecitinib (30 mg/kg; oral; once daily; 12 weeks) malonate can reverse the symptoms of alopecia areata, promote hair regeneration and reduce skin inflammation in the C3H/HeJ mouse alopecia areata model^[3].