2. Academic Validation
  3. Design and Synthesis of Novel Dual Inhibitors for JAK3 and TEC Kinases in Autoimmune Disorders

Design and Synthesis of Novel Dual Inhibitors for JAK3 and TEC Kinases in Autoimmune Disorders

  • J Med Chem. 2025 Jul 10;68(13):13268-13294. doi: 10.1021/acs.jmedchem.4c02288.
Guonan Cui 1,  Rui Li 2 3 4,  Duo An 1,  Yonghua Xie 1,  Chunyan Yu 1,  Wuxin Zou 1,  Yan Xia 1,  Yan Zhang 1,  Kaiwen Feng 1,  Zhankai Xu 1,  Xueying Zheng 1,  Tianshu Jing 1,  Yan Yang 1,  Yanxing Wang 1,  Zhengyu Wang 1,  Lijun Wang 1,  Jianhui Huang 2 3 4,  Zhiqing Zhang 1,  Chengtao Li 1
Affiliations

Affiliations

  • 1 Galixir (Beijing) Co., Ltd., No.48A Zhichun Road, Haidian District, Beijing 100080, P. R. China.
  • 2 School of Pharmaceutical Science and Technology (SPST), Faculty of Medicine, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, P. R. China.
  • 3 International Joint Research Centre for Molecular Sciences, Tianjin University, Tianjin 300072, P. R. China.
  • 4 Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P. R. China.
PMID: 40553489 DOI: 10.1021/acs.jmedchem.4c02288
Abstract

Janus kinase 3 (JAK3) and tyrosine-protein kinase (TEC) play crucial roles in autoimmune diseases. Here, we report the optimization of JAK3/TEC dual covalent inhibitors through a series of rational design strategies. Through the fusion of a fluorine-substituted benzene ring to the piperidine, we achieved compound 8a with improved in vitro activity and selectivity and good drug-like properties. Compound 8a demonstrated excellent therapeutic efficacy in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis orally, with no body weight loss, suggesting a preliminary indication of good safety. These findings support the potential of compound 8a as a promising candidate for the development of new therapies targeting JAK3 and TEC.

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