Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model.
Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model.
复制标题
新型高选择性抑制剂 CHMFL-BTK-11 对 BTK 激酶的不可逆抑制可抑制类风湿关节炎模型中的炎症反应。
DOI：
10.1038/s41598-017-00482-4
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发表时间：
2017-03-28
影响因子：
4.6
通讯作者：
Liu Q
中科院分区：
文献类型：
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作者：
Wu H;Huang Q;Qi Z;Chen Y;Wang A;Chen C;Liang Q;Wang J;Chen W;Dong J;Yu K;Hu C;Wang W;Liu X;Deng Y;Wang L;Wang B;Li X;Gray NS;Liu J;Wei W;Liu Q
BTK在类风湿关节炎（RA）中B细胞受体介导的炎症信号传导中起关键作用。通过合理的设计方法，我们发现了一种高选择性、强效的BTK激酶抑制剂（CHMFL-BTK-11），它通过与BTK Cys481共价键发挥抑制作用。CHMFL-BTK-11能有效阻断Ramos细胞系和分离的人原代B细胞中抗igm刺激的BCR信号。显著抑制LPS刺激的人PBMC细胞TNF-α的产生，对正常PBMC细胞增殖仅有微弱影响。在佐剂诱导的关节炎大鼠模型中，CHMFL-BTK-11通过阻断活化B细胞的增殖，抑制IgG1、IgG2、IgM、IL-6等炎症因子的分泌和PMΦ吞噬作用，刺激IL-10的分泌，改善炎症反应。CHMFL-BTK-11的高特异性使其成为进一步检测BTK介导的RA病理信号的有效药理学工具。
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.