Discovery of novel inhibitors of signal transducer and activator of transcription 3 (STAT3) signaling pathway by virtual screening

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.

Docking mode of compound 9 with STAT3 generated by GLIDE. Compound 9 formed three hydrogen bonds with Gln644, Glu638, and Gln635.Figure optionsDownload as PowerPoint slideHighlights
► Novel enzothiazole scaffold against STAT3 signaling by virtual screening.
► Showed potent activity in STAT3-dependent luciferase reporter assay.
► Showed potent activity in cell line harboring constitutively active STAT3.
► Inhibited (Tyr705) phosphorylation of STAT3.
► Had no obvious effect on upstream tyrosine kinases.