Design and Synthesis of Novel Dual Inhibitors for JAK3 and TEC Kinases in Autoimmune Disorders
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 <b>8a</b> with improved <i>in vitro</i> activity and selectivity and good drug-like properties. Compound <b>8a</b> 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 <b>8a</b> as a promising candidate for the development of new therapies targeting JAK3 and TEC.
Authors
- Yanxing Wang (ORCID: https://orcid.org/0000-0002-9523-0030)
- Xueying Zheng (ORCID: https://orcid.org/0000-0001-7386-4609)
- Zhiqing Zhang (ORCID: https://orcid.org/0000-0002-9306-3267)
- Jianhui Huang (ORCID: https://orcid.org/0000-0001-7281-663X)
- Zijian Xu (ORCID: https://orcid.org/0000-0002-5846-8074)
- Yang Yan (ORCID: https://orcid.org/0000-0001-7694-2801)
- Lijun Wang (ORCID: https://orcid.org/0000-0002-8914-1031)
- Zhenyu Wang (ORCID: https://orcid.org/0000-0001-9187-1028)
- Rui Li (ORCID: https://orcid.org/0000-0003-2196-8435)
- Yonghua Xie
- Yan Zhang (ORCID: https://orcid.org/0000-0003-3183-0034)
- Chengtao Li (ORCID: https://orcid.org/0000-0003-2346-2753)
- Chunyan Yu
- Duo An
- Guonan Cui
- Kaiwen Feng
- Tianshu Jing
- Wuxin Zou
Institutions
- Tianjin University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-06-24
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02288
- Citations
- 2
- Primary Topic
- Chronic Lymphocytic Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 3.25