S14-95, a novel inhibitor of the JAK/STAT pathway from a Penicillium species

Abstract

In a search for new inhibitors of the IFN-γ mediated signal transduction in HeLa S3 cells using secreted alkaline phosphatase (SEAP) as reporter gene, a novel compound, designated as S14-95 was isolated from fermentations of the imperfect fungus Penicillium sp. 14-95. The compound inhibits the IFN-γ mediated expression of the reporter gene with IC50 values of 2.5 - 5 μg/ml (5.4 - 10.8 μM). Furthermore the compound inhibited the expression of the proinflammatory enzymes COX-2 and NOS II at 5 μg/ml (10.8 μM) in LPS/IFN-γ stimulated J774 mouse macrophages. Studies on the mode of action of the compound revealed that the inhibition of the IFN-γ dependent signaling pathway is caused by an inhibition of the phosphorylation of the STAT1 α transcription factor. In addition, S14-95 inhibited the activation of the p38 MAP kinase, which is involved in the inducible expression of many proinflammatory genes.