2. Academic Validation
  3. 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

  • Sci Rep. 2017 Mar 28;7(1):466. doi: 10.1038/s41598-017-00482-4.
Hong Wu 1 2,  Qiong Huang 3,  Ziping Qi 1,  Yongfei Chen 1,  Aoli Wang 1 2,  Cheng Chen 1,  Qianmao Liang 1 4,  Jinghua Wang 5,  Wensheng Chen 3,  Jin Dong 3,  Kailin Yu 1 2,  Chen Hu 1 2,  Wenchao Wang 1,  Xiaochuan Liu 1 4,  Yuanxin Deng 1,  Li Wang 1 2,  Beilei Wang 1 2,  Xiaoxiang Li 6,  Nathanael S Gray 5,  Jing Liu 7,  Wei Wei 8,  Qingsong Liu 9 10
Affiliations

Affiliations

  • 1 High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China.
  • 2 University of Science and Technology of China, P.R. China, Anhui, Hefei, 230036, P.R. China.
  • 3 Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui collaborative innovation center of anti-inflammatory and immune medicine, Hefei, 230032, P.R. China.
  • 4 Department of Chemistry, University of Science and Technology of China, Anhui, Hefei, 230036, P.R. China.
  • 5 Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Ave, SGM 628, Boston, MA, 02115, USA.
  • 6 Anhui New Star Pharmaceutical Inc., Science Road 110, Hefei, Anhui, 230000, P.R. China.
  • 7 High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China. jingliu@hmfl.ac.cn.
  • 8 Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui collaborative innovation center of anti-inflammatory and immune medicine, Hefei, 230032, P.R. China. wwei@ahmu.edu.cn.
  • 9 High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China. qsliu97@hmfl.ac.cn.
  • 10 University of Science and Technology of China, P.R. China, Anhui, Hefei, 230036, P.R. China. qsliu97@hmfl.ac.cn.
PMID: 28352114 DOI: 10.1038/s41598-017-00482-4
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.

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