title: DBM1285 suppresses tumor necrosis factor alpha production by blocking p38 mitogen-activated protein kinase/mitogen-activated protein kinase-activated protein kinase 2 signaling pathway.
abstract: Tumor necrosis factor alpha (TNF-alpha) is a major inflammatory cytokine that plays an important role in the development of various inflammatory diseases. TNF-alpha has been considered as a potential therapeutic target for the treatment of chronic inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. In this study, we report that cyclopropyl-{4-[4-(4-fluorophenyl)-2-piperidin-4-yl-thiazol-5-yl]pyrimidin-2-yl}amine (DBM1285) is a novel inhibitor of TNF-alpha production. DBM1285 concentration-dependently inhibited lipopolysaccharide (LPS)-induced TNF-alpha secretion in various cells of macrophage/monocyte lineage, including mouse bone marrow macrophages, THP-1 cells, and RAW 264.7 cells. However, LPS-induced mRNA expression of TNF-alpha was not affected by DBM1285 in these cells. Further studies demonstrated that the inhibitory effect of DBM1285 on TNF-alpha production might be mediated by post-transcriptional regulation through the modulation of the p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase 2 (MK2) signaling pathway. We also confirmed that DBM1285 directly inhibits p38 MAPK enzymatic activity. In vivo administration of DBM1285 inhibited LPS-induced increase in the plasma level of TNF-alpha in mice. Whole-blood in vivo target inhibition assay also revealed that DBM1285 attenuates p38 MAPK activity after oral administration in mice. Moreover, DBM1285 suppressed zymosan-induced inflammation and adjuvant-induced arthritis in murine models. Collectively, these results suggest that DBM1285 inhibits TNF-alpha production, at least in part, by blocking the p38 MAPK/MK2 pathway. Furthermore, in vivo results suggest that DBM1285 might be a possible therapeutic candidate for the treatment of TNF-alpha-related chronic inflammatory diseases.
authors.affiliation: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk, Republic of Korea.
authors.forename: Jong Soon
authors.initials: JS
authors.lastname: Kang
authors.forename: Hwan Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: In Young
authors.initials: IY
authors.lastname: Choi
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.forename: Yeo Dae
authors.initials: YD
authors.lastname: Yoon
authors.forename: Hyunju
authors.initials: H
authors.lastname: Lee
authors.forename: Ki Hwan
authors.initials: KH
authors.lastname: Park
authors.forename: Ig Jun
authors.initials: IJ
authors.lastname: Cho
authors.forename: Chang Woo
authors.initials: CW
authors.lastname: Lee
authors.forename: Kiho
authors.initials: K
authors.lastname: Lee
authors.forename: Ki Hoon
authors.initials: KH
authors.lastname: Lee
authors.forename: Song-Kyu
authors.initials: SK
authors.lastname: Park
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D019070:Cell Lineage; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines; D012333:RNA, Messenger; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C551469:cyclopropyl-(4-(4-(4-fluorophenyl)-2-piperidin-4-yl-thiazol-5-yl)pyrimidin-2-yl)amine