Discovery of potent STAT3 inhibitors using structure-based virtual screening, molecular dynamic simulation, and biological evaluation

INTRODUCTION: Signal transducer and activator of transcription 3 (STAT3) is ubiquitously hyper-activated in numerous cancers, rendering it an appealing target for therapeutic intervention. METHODS AND RESULTS: In this study, using structure-based virtual screening complemented by molecular dynamics simulations, we identified ten potential STAT3 inhibitors. The simulations pinpointed compounds 8, 9, and 10 as forming distinct hydrogen bonds with the SH2 domain of STAT3. In vitro cytotoxicity assays highlighted compound 4 as a potent inhibitor of gastric cancer cell proliferation across MGC803, KATO III, and NCI-N87 cell lines. Further cellular assays substantiated the ability of compound 4 to attenuate IL-6-mediated STAT3 phosphorylation at Tyr475. Additionally, oxygen consumption rate assays corroborated compound 4's deleterious effects on mitochondrial function. DISCUSSION: Collectively, our findings position compound 4 as a promising lead candidate warranting further exploration in the development of anti-gastric cancer therapeutics.