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 assay showed that compound 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, could inhibit the phosphorylation of STAT3 and the binding affinity was determined by the SPR assay ( = 8.30 μM). Molecule docking studies suggested a plausible binding mode between and the SH2 domain, in which the piperidine fragment and the terminal hydroxy group of 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.