title: Discovery of novel inhibitors of signal transducer and activator of transcription 3 (STAT3) signaling pathway by virtual screening.
abstract: Inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling pathway has been considered a novel therapeutic strategy to treat human cancers that harbor aberrantly-active STAT3. In this study, nearly 204,000 compounds in Specs database were screened by virtual screening, and samples of top 100 compounds identified as candidate small-molecule inhibitors of STAT3 were evaluated by STAT3-dependent luciferase reporter assay as well as other cell-based assays. A benzothiazole core scaffold containing compound, 9, was identified as an inhibitor of IL-6/STAT3 signaling with an IC50 of 3.567 μM. It is the first time to discover benzothiazole scaffold as a potent STAT3 signaling inhibitor. We further investigated the (structure-activity relationship) SAR of the benzothiazole analogues, and discovered compound 16w as a better small-molecule inhibitor. Both compounds inhibited the phosphorylation of STAT3 and had no obvious effect on upstream JAK2 kinase.
authors: School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors: Mingming
authors: M
authors: Zhang
authors: Weiliang
authors: W
authors: Zhu
authors: Yingxia
authors: Y
authors: Li
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D015394:Molecular Structure; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000093242:Interleukin-6 Inhibitors
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D054852:Small Molecule Libraries; D000093242:Interleukin-6 Inhibitors; C494086:STAT3 protein, human