Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model
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...
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2017
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oai:doaj.org-article:ace32d39a1da436aaa24ae8fb665ca2d2021-12-02T12:30:17ZIrreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model10.1038/s41598-017-00482-42045-2322https://doaj.org/article/ace32d39a1da436aaa24ae8fb665ca2d2017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00482-4https://doaj.org/toc/2045-2322Abstract 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.Hong WuQiong HuangZiping QiYongfei ChenAoli WangCheng ChenQianmao LiangJinghua WangWensheng ChenJin DongKailin YuChen HuWenchao WangXiaochuan LiuYuanxin DengLi WangBeilei WangXiaoxiang LiNathanael S. GrayJing LiuWei WeiQingsong LiuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017) |
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DOAJ |
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Medicine R Science Q Hong Wu Qiong Huang Ziping Qi Yongfei Chen Aoli Wang Cheng Chen Qianmao Liang Jinghua Wang Wensheng Chen Jin Dong Kailin Yu Chen Hu Wenchao Wang Xiaochuan Liu Yuanxin Deng Li Wang Beilei Wang Xiaoxiang Li Nathanael S. Gray Jing Liu Wei Wei Qingsong Liu Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model |
| description |
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. |
| format |
article |
| author |
Hong Wu Qiong Huang Ziping Qi Yongfei Chen Aoli Wang Cheng Chen Qianmao Liang Jinghua Wang Wensheng Chen Jin Dong Kailin Yu Chen Hu Wenchao Wang Xiaochuan Liu Yuanxin Deng Li Wang Beilei Wang Xiaoxiang Li Nathanael S. Gray Jing Liu Wei Wei Qingsong Liu |
| author_facet |
Hong Wu Qiong Huang Ziping Qi Yongfei Chen Aoli Wang Cheng Chen Qianmao Liang Jinghua Wang Wensheng Chen Jin Dong Kailin Yu Chen Hu Wenchao Wang Xiaochuan Liu Yuanxin Deng Li Wang Beilei Wang Xiaoxiang Li Nathanael S. Gray Jing Liu Wei Wei Qingsong Liu |
| author_sort |
Hong Wu |
| title |
Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model |
| title_short |
Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model |
| title_full |
Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model |
| title_fullStr |
Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model |
| title_full_unstemmed |
Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model |
| title_sort |
irreversible inhibition of btk kinase by a novel highly selective inhibitor chmfl-btk-11 suppresses inflammatory response in rheumatoid arthritis model |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/ace32d39a1da436aaa24ae8fb665ca2d |
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