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 α(TNF-α) is a major inflammatory cytokine that plays an important role in the development of various inflammatory diseases. TNF-α 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-ylthiazol-5-yl]pyrimidin-2-yl} amine (DBM1285) is a novel inhibitor of TNF-α production. DBM1285 concentration-dependently inhibited lipopolysaccharide (LPS)-induced TNF-α secretion in various cells of macrophage/monocyte lineage, including mouse bone marrow macrophages, THP-1 cells, and RAW264.7 cells. However, LPS-induced mRNA expression of TNF-α was not affected by DBM1285 in these cells. Further studies demonstrated that the inhibitory effect of DBM1285 on TNF-α production might be mediated by post-transcriptional regulation through the modulation of the p38 mitogenactivated 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-α 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-α 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-α-related chronic inflammatory diseases.