Discovery of phenylacetamide derivatives as novel STAT3 antagonists.

Signal transducer and activator of transcription 3 (STAT3) is a central transcription factor in the JAK-STAT signaling axis and is commonly considered to be an anti-cancer drug target. However, no inhibitors that directly target STAT3 have been approved for use in patients. Targeting STAT3 SH2 domain and DNA-binding domain remain the two principle strategies when developing STAT3 inhibitors. In this study, a series of compounds with a phenylacetamide core were designed, synthesized, and biologically evaluated. Two fluorescence polarization (FP) assays were used, where STAT3:DNA FP assay was to understand inhibition of STAT3 DNA-binding potential, whereas STAT3:phosphopeptide FP assay was to understand abrogation of STAT3 dimerization potential. The FP findings showed that the phenylacetamide derivatives were prone to inhibit STAT3 dimerization than STAT3 DNA-binding, showing selectivity over the STAT3 SH2 domain. Compounds P10, P15, and P21 showed potent STAT3 dimerization inhibition with FP-determined IC