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 IC₅₀ values of ~15.6, ~29.4, ~6.49 μM respectively. Molecular docking results showed that compounds P10, P15, and P21 may bind between the Linker and SH2 domains, and they displayed potential hydrogen bonding in the binding pocket. Prediction results of drug-likeness and physiochemical property values warrant P10, P15, and P21 to be further investigated.