The selective M-CSF receptor tyrosine kinase inhibitor Ki20227 suppresses experimental autoimmune encephalomyelitis.
Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), can be induced by the immunization of mice with myelin antigens in the form of myelin oligodendrocyte glycoprotein (MOG). Macrophage colony-stimulating factor (M-CSF) is required for the development of individual mononuclear phagocyte populations and is involved in the immune response. We previously reported that Ki20227 (N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N'-[1-(1,3-thiazole-2-yl)ethyl]urea) is a highly selective M-CSF receptor (c-fms) tyrosine kinase inhibitor. In our current study, we investigated whether Ki20227 has suppressive effects upon EAE and indeed found that this drug significantly reduced the severity of this disease both preventively and therapeutically. Notably also, Ki20227 treatments inhibited the turn-over/expansion of myeloid cells provoked by the immunization and subsequent MOG-specific T cell responses in our EAE animal model. These findings suggest that M-CSF plays a pivotal role in the development of EAE and that Ki20227 and its derivatives may be candidate drugs for the treatment of human MS.
Uemura
Yasunori
Y
Discovery Research Laboratories, Kirin Pharma Company Limited, 3 Miyahara, Takasaki, Gunma, 370-1295, Japan. yasunori_uemura@kirin.co.jp
Ohno
Hiroaki
H
Ohzeki
Yumiko
Y
Takanashi
Hiromi
H
Murooka
Hideko
H
Kubo
Kazuo
K
Serizawa
Isao
I
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D005434:Flow Cytometry / Q000379:methods; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D013116:Spinal Cord / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects; D013844:Thiazoles / Q000627:therapeutic use*; D013997:Time Factors
D015703:Antigens, CD; D016207:Cytokines; C571326:MOG protein, human; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; C517050:N-(4-((6,7-dimethoxy-4-quinolyl)oxy)-2-methoxyphenyl)-N'-(1-(1,3-thiazole-2-yl)ethyl)urea; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D013844:Thiazoles