1. Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model
- Author
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Wu, Hong, Huang, Qiong, Qi, Ziping, Chen, Yongfei, Wang, Aoli, Chen, Cheng, Liang, Qianmao, Wang, Jinghua, Chen, Wensheng, Dong, Jin, Yu, Kailin, Hu, Chen, Wang, Wenchao, Liu, Xiaochuan, Deng, Yuanxin, Wang, Li, Wang, Beilei, Li, Xiaoxiang, Gray, Nathanael S., Liu, Jing, Wei, Wei, and Liu, Qingsong
- Abstract
BTK plays a critical role in the B cell receptor mediated inflammatory signaling in the rheumatoid arthritis (RA). Through a rational design approach we discovered a highly selective and potent BTK kinase inhibitor (CHMFL-BTK-11) which exerted its inhibitory efficacy through a covalent bond with BTK Cys481. CHMFL-BTK-11 potently blocked the anti-IgM stimulated BCR signaling in the Ramos cell lines and isolated human primary B cells. It significantly inhibited the LPS stimulated TNF-α production in the human PBMC cells but only weakly affecting the normal PBMC cell proliferation. In the adjuvant-induced arthritis rat model, CHMFL-BTK-11 ameliorated the inflammatory response through blockage of proliferation of activated B cells, inhibition of the secretion of the inflammatory factors such as IgG1, IgG2, IgM, IL-6 and PMΦ phagocytosis, stimulation of secretion of IL-10. The high specificity of CHMFL-BTK-11 makes it a useful pharmacological tool to further detect BTK mediated signaling in the pathology of RA.
- Published
- 2017
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