Discovery of Juglone Derivatives as Novel STAT3 Inhibitors with Potent Suppression of Cancer Cell Stemness against Breast Cancer

Breast cancer stem cells (BCSCs) are pivotal in tumor initiation, progression, and therapeutic resistance, underscoring the need for targeted interventions. Signal transducer and activator of transcription 3 (STAT3) has been implicated in maintaining cancer stemness, representing a compelling therapeutic target. Here, we describe the structure-guided optimization of Juglone, yielding novel STAT3 inhibitors with improved potency. The representative compound 35 (YZ-35) demonstrated potent STAT3 phosphorylation and exhibited nanomolar affinity in binding assays (IC₅₀ = 190 nM). YZ-35 exhibited remarkable antiproliferative activity across multiple breast cancer cell lines and selectively suppressed BCSC self-renewal, outperforming TTI-101 and matching BBI-608 in potency. In vivo, YZ-35 achieved approximately 90% tumor growth inhibition (10 mg/kg) in xenograft models, with reduced toxicity versus paclitaxel. Mechanistic studies confirmed STAT3 pathway disruption and BCSC depletion. These results highlight YZ-35 as a natural product-derived STAT3 inhibitor with dual antitumor and anti-CSC activity, offering a translational strategy for refractory BRCA.