title: Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model.
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.
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China.|University of Science and Technology of China, P.R. China, Anhui, Hefei, 230036, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Huang
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China.
authors.forename: Ziping
authors.initials: Z
authors.lastname: Qi
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China.
authors.forename: Yongfei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China.|University of Science and Technology of China, P.R. China, Anhui, Hefei, 230036, P.R. China.
authors.forename: Aoli
authors.initials: A
authors.lastname: Wang
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China.|Department of Chemistry, University of Science and Technology of China, Anhui, Hefei, 230036, P.R. China.
authors.forename: Qianmao
authors.initials: Q
authors.lastname: Liang
authors.affiliation: Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Ave, SGM 628, Boston, MA, 02115, USA.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Jin
authors.initials: J
authors.lastname: Dong
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China.|University of Science and Technology of China, P.R. China, Anhui, Hefei, 230036, P.R. China.
authors.forename: Kailin
authors.initials: K
authors.lastname: Yu
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China.|University of Science and Technology of China, P.R. China, Anhui, Hefei, 230036, P.R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Hu
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Wang
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China.|Department of Chemistry, University of Science and Technology of China, Anhui, Hefei, 230036, P.R. China.
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China.
authors.forename: Yuanxin
authors.initials: Y
authors.lastname: Deng
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China.|University of Science and Technology of China, P.R. China, Anhui, Hefei, 230036, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China.|University of Science and Technology of China, P.R. China, Anhui, Hefei, 230036, P.R. China.
authors.forename: Beilei
authors.initials: B
authors.lastname: Wang
authors.affiliation: Anhui New Star Pharmaceutical Inc., Science Road 110, Hefei, Anhui, 230000, P.R. China.
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Ave, SGM 628, Boston, MA, 02115, USA.
authors.forename: Nathanael S
authors.identifier: 0000-0001-5354-7403
authors.initials: NS
authors.lastname: Gray
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China. jingliu@hmfl.ac.cn.
authors.forename: Jing
authors.identifier: 0000-0001-9513-3591
authors.initials: J
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, 230031, Anhui, P.R. China. qsliu97@hmfl.ac.cn.|University of Science and Technology of China, P.R. China, Anhui, Hefei, 230036, P.R. China. qsliu97@hmfl.ac.cn.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001169:Arthritis, Experimental; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human