化学
类风湿性关节炎
布鲁顿酪氨酸激酶
药理学
关节炎
癌症研究
免疫学
生物化学
酪氨酸激酶
信号转导
医学
作者
Xiaobao Fang,Chunxiao Liu,Kun Zhang,Wanping Yang,Zewen Wu,Shige Shen,Yule Ma,Xihong Lu,Yadong Chen,Tao Lü,Qinghua Hu,Yulei Jiang
标识
DOI:10.1016/j.ejmech.2022.114940
摘要
Bruton's tyrosine kinase (BTK) plays a crucial role in adaptive and immune responses by modulating B-cell, Fc, toll-like, and chemokine receptor signaling pathways. BTK inhibition is a promising therapeutic approach for the treatment of inflammatory and autoimmune diseases. The development of novel, highly selective, and less toxic BTK inhibitors may be beneficial for the treatment of autoimmune diseases with unmet medical needs. In this study, structure-based drug design was used to discover a series of novel, potent, and selective covalent BTK inhibitors with a 1,4,5,6,8-pentaazaacenaphthylen scaffold. Among them, compound 36R exhibited high kinase selectivity, long target occupancy time, appropriate pharmacokinetic properties, and dose-dependent efficacy in a rat model of collagen-induced arthritis. Therefore, 36R is a novel BTK inhibitor requiring further development for the treatment of autoimmune diseases.
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