Identification of a dual JAK3/TEC family kinase inhibitor for atopic dermatitis therapy.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by recurrent eczematous lesions and severe itching, for which clinical treatments are limited. Selectively inhibiting Janus Kinase 3 (JAK3) and tyrosine kinase expressed in hepatocellular carcinoma (TEC) family kinases is proposed as a promising strategy to treat AD with possible reduced side effects and enhanced efficacy. In this study, we developed a dual JAK3/TEC family kinase inhibitor ZZB, which demonstrated potent inhibitory activity with IC₅₀ values of 0.89 nM against JAK3 and 11.56 nM against TEC kinase interleukin-2-inducible T-cell kinase (ITK). Docking studies revealed that ZZB forms a covalent bond with the unique cysteine residue at position 909 (Cys⁹⁰⁹) in JAK3 and Cys⁴⁴² in ITK. Utilizing human peripheral blood mononuclear cells, we discovered ZZB selectively inhibits JAK3-dependent cytokines signaling and ITK-mediated CD4⁺ T cell activation. Moreover, in vitro studies indicated ZZB significantly suppresses the proliferation and differentiation of CD4⁺ T cells, as well as the cytolytic function of CD8⁺ T cells and NK cells. We then conducted a pharmacokinetic study in mice and observed a favorable pharmacokinetic profile for ZZB. In a mouse model of AD induced by repeated application of 2,4-dinitrochlorobenzene to the shaved dorsal skin, oral administration of ZZB (100 mg/kg) markedly improved skin condition and reduced immune cell infiltration, matching the efficacy of the positive drug dexamethasone. We conclude that the JAK3/TEC kinase inhibitor ZZB is a highly promising candidate for the treatment of AD.