TMC-264, a Novel Inhibitor of STAT6 Activation Produced by Phoma sp. TC 1674

• Published in: Journal of antibiotics Vol. 56; no. 6; pp. 513 - 519
• Main Authors: SAKURAI, MASAAKI, NISHIO, MAKI, YAMAMOTO, KOUZOU, OKUDA, TORU, KAWANO, KIMIO, OHNUKI, TETSUO
• Format: Journal Article
• Language: English
• Published: TOKYO JAPAN ANTIBIOTICS RESEARCH ASSOCIATION 01.06.2003; JAPAN ANTIBIOT RES ASSN; Japan Antibiotics Research Association
• Subjects: Biological and medical sciences; Biotechnology & Applied Microbiology; Chromatography, High Pressure Liquid; Drug Interactions; Fermentation; HeLa Cells; Heterocyclic Compounds, 3-Ring - isolation & purification; Heterocyclic Compounds, 3-Ring - pharmacology; Histamine and antagonists. Allergy; Humans; Immunology; Interleukin-4 - pharmacology; Life Sciences & Biomedicine; Medical sciences; Microbiology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phoma; Phosphorylation - drug effects; Science & Technology; Signal Transduction - drug effects; STAT6 Transcription Factor; Trans-Activators - antagonists & inhibitors; CELLS; FUNGUS; GENE; TRANSCRIPTION; IL-4; MICE; SWITCH; EXPRESSION; SIGNAL TRANSDUCER; Identification; Fermentation; In vitro; Biological activity; Antiallergic; Strain; Fungi; Antibiotic; Phoma; Transcription factor STAT6; Microbial origin; Fungi Imperfecti; Mechanism of action; Thallophyta
• ISSN: 0021-8820; 1881-1469
• DOI: 10.7164/antibiotics.56.513

A novel inhibitor of STAT6 activation, named as TMC-264 (1), was discovered from the fermentation broth of Phoma sp. TC 1674. Based on spectroscopic analyses, TMC-264 was found to be a novel tricyclic polyketide with chloro-1H-dibenzo[b, d]pyran-4, 6-dione. TMC-264 suppressed expression of IL-4 driven luciferase and germline Cε mRNA with IC50 values of 0.3μM and 0.4μM, respectively. TMC-264 exhibited a potent inhibitory activity against tyrosine phosphorylation of STAT6 with an IC50 value of 1.6μM, whereas TMC-264 weakly inhibited tyrosine phosphorylation of STAT5 with an IC50 value of 16μM, but did not inhibit the phosphorylation of STAT1 up to 40μM. TMC-264 blocked formation of the complexes between phosphorylated STAT6 and STAT6 oligonucleotides in a dose dependent manner, while TMC-264 did not affect the formation of phosphorylated STAT1/STAT1 oligonucleotides complexes. These results suggested that TMC-264 selectively inhibited IL-4 signaling by interfering both of phosphorylation of STAT6 and binding of the phosphorylated STAT6 to the recognition sequence.