Identification of a novel competitive inhibitor of p38α MAPK by a human PBMC screen

The pro-inflammatory cytokines TNF-α and IL-1β are two of the important mediators involved in the several chronic inflammatory diseases. We used the release of TNF-α and IL-1β from lipopolysaccharide-stimulated human PBMC as inflammatory indexes to discover the potential anti-inflammatory candidates. Among near 500 chemical compounds, MT4 had the suppressive action on the release of TNF-α and IL-1β in PBMC with IC50 values of 22 and 44 nM, respectively. After verified the MT4 inhibitory mechanism, the results revealed that p38α and p38β MAPK activity was inhibited by MT4 with an IC50 value of 0.13 and 0.55 μM, respectively. Further characterization of enzyme kinetics showed the binding mode of MT4 was competitive with the ATP substrate-binding site of p38α MAPK.