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.