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
  • 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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