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Thus, ITK inhibitors have therapeutic potential in T cell\u2010derived allergic airway inflammation. Nevertheless, no ITK inhibitors are currently approved for asthma treatment, warranting the need to excavate potent small\u2010molecule ITK inhibitors. Here, a novel small\u2010molecule ITK inhibitor C\u2010161 was discovered by compound screening. <jats:italic>In silico<\/jats:italic> docking and surface plasmon resonance (SPR) confirmed that C\u2010161 directly binds to the ITK kinase domain. In\u00a0vitro cellular assays demonstrated that C\u2010161 prevents TCR\u2010induced proinflammatory cytokine release as well as activation and differentiation of Th2 and Th17 cells in a dose\u2010dependent manner. In\u00a0vivo assays demonstrated that C\u2010161 administration ameliorates the progression of asthma by mitigating infiltration of inflammatory cells and decreasing mucus and IgE production. Additionally, C\u2010161 markedly suppressed airway inflammation by inhibiting Th2\/Th17\u2010related immune responses with declined IL4, IL5, IL13 and IL17A expression. Collectively, our study uncovers a novel ITK\u2010specific small molecule inhibitor, C\u2010161, as an attractive lead compound for developing drugs to treat asthma.<\/jats:p>","DOI":"10.1111\/imm.70003","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T02:04:54Z","timestamp":1749780294000},"page":"349-362","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Novel Small Molecule <scp>ITK<\/scp> Inhibitor Suppresses Th2\/Th17 Differentiation and Attenuates Airway Inflammation in a Mouse Model of <scp>HDM<\/scp>\u2010Induced Asthma"],"prefix":"10.1111","volume":"176","author":[{"given":"Zhaoxi","family":"Guo","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural Medicines, School of Life Science and Technology China Pharmaceutical University  Nanjing 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