CS12192, a novel JAK3/JAK1/TBK1 inhibitor, attenuates autoimmune dermatoses in murine models.

ABSTRACT

OBJECTIVE: Autoimmune dermatosis (AID) occurs when the body's immune system attacks skin or tissue, leading to various types of skin disorders or injuries. Recent studies show that Janus kinases (JAKs) play critical roles in autoimmune diseases including AID by regulating multiple cytokine signaling pathways. CS12192, a novel JAK3/JAK1/TBK1 inhibitor, has been reported to exert ameliorative effects in rheumatoid arthritis. However, the efficacy of CS12192 on AID is undetermined. This study aims to investigate the therapeutic efficacy of CS12192 on psoriasis (PSO), systemic lupus erythematosus (SLE) and atopic dermatitis (AD) in mouse models. METHODS: Interleukin-23 (IL-23)-induced PSO model, spontaneous SLE model of MRL/MpJ-Faslpr/J (MRL/lpr) mice, and oxazolone (OXA) and dinitrochlorobenzene (DNCB)-induced murine AD models were used for the evaluation of curative effects of CS12192, respectively. The skin lesion, biochemical parameters, ear thickness, ear weight and histopathology were assessed accordingly. RESULTS: In PSO model, mice treated with CS12192 show reduced ear thickness and ear weight as compared with vehicle. In SLE model, CS12192 ameliorates cutaneous parameters such as lymphadenectasis and skin lesion but not systematic parameters such as proteinuria concentration and score, serum dsDNA and BUN concentration. In AD models, CS12192 dose-dependently improves ear swelling and reduces histological scores, exerting equivalent efficacy with baricitinib, a marketed JAK1/JAK2 inhibitor. CONCLUSION: Our findings suggest that the novel JAK3/JAK1/TBK1 inhibitor CS12192 is potentially to alleviate autoimmune dermatosis.