Journal
SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-00482-4
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Funding
- Youth Foundation of National Natural Science Foundation of China [21402207]
- grant of Cross- disciplinary Collaborative Teams Program for Science, Technology and Innovation from Chinese Academy of Sciences
- China Thousand Talents Program
- Hundred Talents Program of the Chinese Academy of Sciences
- National Program for Support of Top-notch Young Professionals
- Key Science and Technology Program of Anhui province, P.R.China [1501041175]
- Hefei Science Center CAS [2016HSC-IU007]
- State Key Program of National Natural Science of China [81330081]
- National Natural Science Foundation of China [81202596, 81603123]
- Postdoctoral innovative talent support program [BX201600169]
- Natural Science Foundation of Anhui province [1608085QH180]
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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-alpha production in the human PBMC cells but only weakly affecting the normal PBMC cell proliferation. In the adjuvantinduced 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 PM Phi 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.
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