Ritlecitinib | JAK3 inhibitor

Ritlecitinib (1792180-81-4) is potent (IC₅₀ = 33 nM) covalent JAK3 inhibitor with exquisite selectivity over other members in its kinase class (JAK1, JAK2, TYK2).^1,2 It also displays excellent kinome selectivity against 305 kinases tested. Ritlecitinib inhibits Th1 and Th17 cell differentiation and function and ameliorates symptoms in rat arthritis and mouse autoimmune encephalomyelitis models.² It selectively targets γc cytokine pathways while preserving JAK1-dependent anti-inflammatory signaling. Ritlecitinib also displays activity against some TEC family kinases (BTK, BMX, ITK, RLK,TEC) leading to inhibition of the cytolytic function of CD8+ T cells and NK cells.³ Low dose Ritlecitinib significantly improved T-cell responses and decreased tumor load in louse cancer models.⁴ It significantly prolonged allograft survival in a mouse cardiac transplantation model.

References/Citations:

1. Thorarensen et al. (2017), Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-0665160) Allowing for the Interrogation of JAK3 Signaling in Humans; J. Med. Chem., 60 1971
2. Telliez 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 3442
3. Xu, et al. (2019), PF-06651600, a Dual JAK3/TEC Family Kinase Inhibitor; ACS Chem. Biol., 14 1235
4. Dammeijer et al. (2022), Low-Dose JAK3 Inhibition Improves Antitumor T-Cell Immunity and Immunotherapy Efficacy; Mol. Cancer Ther., 13 1213715
5. Liu et al. (2025), Novel janus kinase 3 inhibitor ritlecitinib suppresses T and B cell responses to prevent acute cardiac allograft rejection in mice; Clin. Immunol., 273 110445