– STAT3-IN-25 (compound 4c), recognized for its potent inhibition of STAT3 dual phosphorylation, features an indole-containing tetra-aromatic heterocycle scaffold. This orally active inhibitor exhibits impressive inhibitory concentrations, with a luciferase activity IC50 of 5.3 nM and an ATP inhibition IC50 of 4.2 nM. It effectively blocks p-Tyr705 and p-Ser727, leading to the disruption of STAT3’s nuclear transcription and mitochondrial oxidative phosphorylation. By targeting the SH2 domain of STAT3 (K D =21.3 nM), STAT3-IN-25 demonstrates substantial effectiveness in disrupting STAT3 functions at low nanomolar ranges. Additionally, it has shown significant suppressive effects in a pancreatic cancer xenograft model.