Natural Product-Inspired Discovery of Naphthoquinone-Furo-Piperidine Derivatives as Novel STAT3 Inhibitors for the Treatment of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and STAT3 has emerged as an effective drug target for TNBC treatment. Herein, we employed a scaffold-hopping strategy of natural products to develop a series of naphthoquinone-furopiperidine derivatives as novel STAT3 inhibitors. The <i>in vitro</i> assay showed that compound <b>10g</b> possessed higher antiproliferative activity than Cryptotanshinone and Napabucasin against TNBC cell lines, along with lower toxicity and potent antitumor activity in a TNBC xenograft model. Mechanistically, <b>10g</b> could inhibit the phosphorylation of STAT3 and the binding affinity was determined by the SPR assay (<i>K</i>_D = 8.30 μM). Molecule docking studies suggested a plausible binding mode between <b>10g</b> and the SH2 domain, in which the piperidine fragment and the terminal hydroxy group of <b>10g</b> played an important role in demonstrating the success of this evolution strategy. These findings provide a natural product-inspired novel STAT3 inhibitor for TNBC treatment.