S14-95, a novel inhibitor of the JAK/STAT pathway from a Penicillium species.
In a search for new inhibitors of the IFN-gamma 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-gamma mediated expression of the reporter gene with IC50 values of 2.5 to approximately 5 microg/ml (5.4 to approximately 10.8 microM). Furthermore the compound inhibited the expression of the proinflammatory enzymes COX-2 and NOS II at 5 microg/ml (10.8 microM) in LPS/IFN-gamma stimulated J774 mouse macrophages. Studies on the mode of action of the compound revealed that the inhibition of the IFN-gamma dependent signaling pathway is caused by an inhibition of the phosphorylation of the STAT1alpha 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.
Erkel
Gerhard
G
Institut für Biotechnologie und Wirkstoff-Forschung e.V, Erwin-Schrödinger-Str. 56, D-67663 Kaiserslautern, Germany. erkel@ibwf.de
Rether
Jan
J
Anke
Timm
T
Sterner
Olov
O
D000818:Animals; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019169:Jurkat Cells; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins; D051379:Mice; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D010407:Penicillium / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology*; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D015025:Zearalenone / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D050832:Interferon-Stimulated Gene Factor 3; D007527:Isoenzymes; D008565:Membrane Proteins; C471131:S14-95; D014157:Transcription Factors; C079868:gamma interferon activation factor; D015025:Zearalenone; D007371:Interferon-gamma; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases