Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model

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Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model

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Title: Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model
Author: 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; Liu, Qingsong

Note: Order does not necessarily reflect citation order of authors.

Citation: Wu, H., Q. Huang, Z. Qi, Y. Chen, A. Wang, C. Chen, Q. Liang, et al. 2017. “Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model.” Scientific Reports 7 (1): 466. doi:10.1038/s41598-017-00482-4. http://dx.doi.org/10.1038/s41598-017-00482-4.
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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 Version: doi:10.1038/s41598-017-00482-4
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428509/pdf/
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Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:33029934
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