Discovery of pyrazole-based selective covalent ITK inhibitors with In vivo activity
- Eur J Med Chem. 2026 May 30:316:119025. doi: 10.1016/j.ejmech.2026.119025.
- 1. State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, 518055, China.
- 2. State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, 518055, China. Electronic address: [email protected].
Interleukin-2 inducible T-cell kinase (Itk) plays a major role in T cell signaling downstream of the T cell receptor (TCR) and is a promising therapeutic target for inflammatory diseases and T cell-related blood cancers. Herein, a novel series of covalent Itk inhibitors was developed using a structure-based design. The optimized compound 19 demonstrated potent Itk inhibitory activity and effectively suppressed downstream protein phosphorylation as well as IL-2 secretion in Jurkat cells. It exhibits exceptional selectivity over Btk and Other structurally related kinases. Moreover, compound 19 significantly inhibited IL-2 production in both a washout cellular assay and an anti-CD3 mAb-challenged mouse model, with sustained effects superior to its reversible counterpart. Thus, compound 19 represents a valuable tool for the further exploration of the potential benefits of Itk inhibition in basic and translational research.