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
  • 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. [email protected].
  • 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. [email protected].
  • 9. High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China. [email protected].
  • 10. University of Science and Technology of China, P.R. China, Anhui, Hefei, 230036, P.R. China. [email protected].
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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