Wu, HongHuang, QiongQi, ZipingChen, YongfeiWang, AoliChen, ChengLiang, QianmaoWang, JinghuaChen, WenshengDong, JinYu, KailinHu, ChenWang, WenchaoLiu, XiaochuanDeng, YuanxinWang, LiWang, BeileiLi, XiaoxiangGray, NathanaelLiu, JingWei, WeiLiu, Qingsong2017-06-152017Wu, 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.http://nrs.harvard.edu/urn-3:HUL.InstRepos:33029934BTK 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.en-USJournal Article2017-06-1510.1038/s41598-017-00482-4