title: Novel high-throughput screening system for identifying STAT3-SH2 antagonists.
abstract: Constitutive activation of the oncogenic transcription factor STAT3 frequently occurs in various human malignancies. STAT3 activation involves dimerization via intermolecular pTyr-SH2 interaction. Thus, antagonizing this interaction is a feasible approach to inhibit STAT3 activation for cancer therapy. In order to identify selective STAT3 inhibitors, we developed a biochemical HTS system based on AlphaScreen technology, which measures the abilities of test compounds to antagonize pTyr-SH2 interactions. We screened our chemical libraries using this system and identified 5,15-diphenylporphyrin (5,15-DPP) as a selective STAT3-SH2 antagonist. Selective inhibition of STAT3 nuclear translocation and DNA biding activity was observed in cells treated with 5,15-DPP. IL-6-dependent dimerization of STAT3, c-myc promoter binding and c-myc protein expression were all suppressed by 5,15-DPP, whereas no decrement in either expression or phosphorylation level of STAT3 was observed. Thus, the HTS assay system represented herein may be useful for identifying novel STAT3-SH2 antagonists.
authors.affiliation: Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Uehara
authors.forename: Masato
authors.initials: M
authors.lastname: Mochizuki
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsuno
authors.forename: Takeharu
authors.initials: T
authors.lastname: Haino
authors.forename: Akira
authors.initials: A
authors.lastname: Asai
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000302:isolation & purification* / Q000494:pharmacology; D019281:Dimerization; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018909:src Homology Domains / Q000187:drug effects*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; D019061:src-Family Kinases