Discovery of novel JAK3 inhibitors for the treatment of atopic dermatitis

Janus kinase 3 (JAK3), a member of the Janus kinase family, plays a pivotal role in the signaling pathways of various pro-inflammatory cytokines such as IL-2 and IFN-γ. Compared to non-selective JAK inhibitors, selective JAK3 inhibitors specifically target distinct signaling pathways, thereby reducing the broad inhibition of other cytokines and minimizing potential side effects. This selectivity renders them potentially advantageous for the treatment of autoimmune and inflammatory disease. In this study, we describe the discovery of compound X15, a novel JAK3 inhibitor with potent JAK3 inhibitory activity (IC₅₀ = 14.56 nM) and an acceptable pharmacokinetic profile (F = 27.38 %, T_1/2 = 20.33 h). Furthermore, compound X15 alleviated the symptoms of dermatitis in a DNCB-induced atopic dermatitis Balb/c mice model, with reduced ear thickness at a high dose (90 mg/kg, 0.038 mm) compared to the model group (0.106 mm). Preliminary mechanistic studies indicated that compound X15 inhibited the production of inflammatory cytokines IL-2 and IL-6 when compared to the model group. Collectively, our findings suggest that compound X15 is a novel covalent JAK3 inhibitor with promising in vitro and in vivo efficacy, potentially serving as a valuable molecular tool for exploring the biological functions of JAK3.