A Novel Small Molecule ITK Inhibitor Suppresses Th2/Th17 Differentiation and Attenuates Airway Inflammation in a Mouse Model of HDM‐Induced Asthma

ABSTRACT Interleukin (IL)‐2‐inducible T cell kinase (ITK) is essential for T cell receptor (TCR) signalling and plays a pivotal role in asthma pathogenesis. Thus, ITK inhibitors have therapeutic potential in T cell‐derived allergic airway inflammation. Nevertheless, no ITK inhibitors are currently approved for asthma treatment, warranting the need to excavate potent small‐molecule ITK inhibitors. Here, a novel small‐molecule ITK inhibitor C‐161 was discovered by compound screening. In silico docking and surface plasmon resonance (SPR) confirmed that C‐161 directly binds to the ITK kinase domain. In vitro cellular assays demonstrated that C‐161 prevents TCR‐induced proinflammatory cytokine release as well as activation and differentiation of Th2 and Th17 cells in a dose‐dependent manner. In vivo assays demonstrated that C‐161 administration ameliorates the progression of asthma by mitigating infiltration of inflammatory cells and decreasing mucus and IgE production. Additionally, C‐161 markedly suppressed airway inflammation by inhibiting Th2/Th17‐related immune responses with declined IL4, IL5, IL13 and IL17A expression. Collectively, our study uncovers a novel ITK‐specific small molecule inhibitor, C‐161, as an attractive lead compound for developing drugs to treat asthma.