RGD Reference Report - Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model. - Rat Genome Database

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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.

Authors: 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 
Citation: Wu H, etal., Sci Rep. 2017 Mar 28;7(1):466. doi: 10.1038/s41598-017-00482-4.
RGD ID: 151665126
Pubmed: PMID:28352114   (View Abstract at PubMed)
PMCID: PMC5428509   (View Article at PubMed Central)
DOI: DOI:10.1038/s41598-017-00482-4   (Journal Full-text)

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 PMĪ¦ 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.

Objects Annotated

Genes (Rattus norvegicus)
Btk  (Bruton tyrosine kinase)


Additional Information