Design and System of Novel Dual Inhibitors for JAK3 и TEC Kinases в аутоиммунных расстройствах.
Обработка статьи · этапы, ошибки и управление
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История · было → стало
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Cui Guonan, Li Rui, An Duo, Xie Yonghua, Yu Chunyan, Zou Wuxin, Xia Yan, Zhang Yan, Feng Kaiwen, Xu Zhankai, Zheng Xueying, Jing Tianshu, Yang Yan, Wang Yanxing, Wang Zhengyu, Wang Lijun, Huang Jianhui, Zhang Zhiqing, Li Chengtao
Аннотация
Оригинал публикации
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 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.