title: TMC-264, a novel inhibitor of STAT6 activation produced by Phoma sp. TC 1674.
abstract: 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 Cepsilon mRNA with IC50 values of 0.3 microM and 0.4 microM, respectively. TMC-264 exhibited a potent inhibitory activity against tyrosine phosphorylation of STAT6 with an IC50 value of 1.6 microM, whereas TMC-264 weakly inhibited tyrosine phosphorylation of STAT5 with an IC50 value of 16 microM, but did not inhibit the phosphorylation of STAT1 up to 40 microM. 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.
authors.affiliation: Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-50 Kawagishi-2-chome, Toda-shi, Saitama 335-8505, Japan. sakura@tanabe.co.jp
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sakurai
authors.forename: Maki
authors.initials: M
authors.lastname: Nishio
authors.forename: Kouzou
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Toru
authors.initials: T
authors.lastname: Okuda
authors.forename: Kimio
authors.initials: K
authors.lastname: Kawano
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ohnuki
mesh_terms: D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D005285:Fermentation; D006367:HeLa Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000037:antagonists & inhibitors*
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C476504:TMC-264; D015534:Trans-Activators; D015847:Interleukin-4