title: JTE-852, a novel spleen tyrosine kinase inhibitor, blocks mediator secretion from mast cells with immunoglobulin E crosslinking.
abstract: Mast cells stimulated by immunoglobulin E (IgE)-crosslinking secrete mediators, which are mainly categorized into three groups: granule contents, arachidonate metabolites, and cytokines. These mediators play important roles in pathogenesis of allergic diseases; indeed, some conventional drugs which target the mediators are used in clinical practices. However, these drugs are not yet sufficient enough in their efficacy. That is because most of them are blockers of single mediators and are unable to prevent simultaneously various reactions caused by the three group mediators. Spleen tyrosine kinase (Syk) is a non-receptor protein tyrosine kinase. In mast cells, Syk locates at almost top of the signal cascades induced by IgE-crosslinking and plays pivotal roles in secretion of the three groups of mediators. Therefore, inhibition of Syk would suppress the secretion of all the mediators from mast cells and be a promising-treatment strategy for allergic diseases. In the present study, we characterized pharmacological profiles of JTE-852, which was identified as a novel Syk inhibitor. JTE-852 inhibited kinase activity of Syk in an adenosine 5'-triphosphate (ATP)-competitive fashion. JTE-852 also blocked the secretion of granule contents, arachidonate metabolites, and cytokines from mast cells stimulated by IgE-crosslinking, with similar potencies. The results suggest that JTE-852 is supposed to prevent various allergic reactions caused by the three group mediators in vivo. In fact, oral gavage of JTE-852 attenuated an allergic reaction mediated by histamine, which is a representative of the three groups of mediators. JTE-852 is expected to be a novel, highly-efficacious, and orally available anti-allergic drug.
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan. Electronic address: toshinobu.kato@jt.com.
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Kato
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Iwasaki
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors.forename: Hatsue
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyagawa
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuo
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hata
authors.affiliation: Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors.forename: Mutsuyoshi
authors.initials: M
authors.lastname: Matsushita
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D007073:Immunoglobulin E / Q000276:immunology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000072377:Syk Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000631:Aminopyridines; C000617176:JTE-852; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D007073:Immunoglobulin E; D000072377:Syk Kinase
keywords: Allergy; IgE-crosslinking; JTE-852; Mast cell; Mediator; Spleen tyrosine kinase