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Identification of a dual JAK3/TEC family kinase inhibitor for atopic dermatitis therapy
Yiwen Du1, Longling Wang1, Jingmei Zhou1
1Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Abstract:
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.
Insights
A new drug, ZZB, effectively treats atopic dermatitis (AD) by inhibiting Janus Kinase 3 (JAK3) and TEC family kinases. This dual-action inhibitor shows promise for managing AD with improved efficacy and safety.
Area of Science:
- Immunology
- Dermatology
- Pharmacology
Background:
- Atopic dermatitis (AD) is a chronic inflammatory skin condition with limited treatment options.
- Targeting Janus Kinase 3 (JAK3) and TEC family kinases offers a potential therapeutic strategy for AD.
- Developing selective inhibitors can enhance efficacy and reduce side effects.
Purpose of the Study:
- To develop and evaluate a novel dual JAK3/TEC family kinase inhibitor, ZZB, for atopic dermatitis treatment.
- To assess the inhibitory activity, mechanism of action, and in vivo efficacy of ZZB.
- To investigate the pharmacokinetic profile and therapeutic potential of ZZB in an AD mouse model.
Main Methods:
- Development of ZZB, a dual JAK3/TEC family kinase inhibitor.
- In vitro assays to determine IC50 values against JAK3 and TEC kinase (ITK).
- Docking studies to elucidate ZZB's binding mechanism with JAK3 and ITK.
- Experiments using human peripheral blood mononuclear cells to assess ZZB's effects on cytokine signaling and T cell activation.
- In vitro studies on T cell proliferation/differentiation and CD8+/NK cell function.
- Pharmacokinetic studies in mice and efficacy evaluation in a 2,4-dinitrochlorobenzene-induced AD mouse model.
Main Results:
- ZZB demonstrated potent inhibition of JAK3 (IC50 = 0.89 nM) and ITK (IC50 = 11.56 nM).
- ZZB forms a covalent bond with Cys909 in JAK3 and Cys442 in ITK.
- ZZB selectively inhibited JAK3-dependent cytokine signaling and ITK-mediated CD4+ T cell activation.
- In vitro, ZZB suppressed CD4+ T cell proliferation/differentiation and CD8+/NK cell cytolytic function.
- ZZB exhibited a favorable pharmacokinetic profile in mice.
- Oral ZZB administration significantly improved skin condition and reduced immune cell infiltration in an AD mouse model, comparable to dexamethasone.
Conclusions:
- ZZB is a potent dual JAK3/TEC family kinase inhibitor with a promising therapeutic profile for atopic dermatitis.
- ZZB's mechanism involves selective inhibition of key immune pathways implicated in AD pathogenesis.
- ZZB demonstrates significant efficacy in a preclinical AD model, supporting its potential as a novel treatment option.
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