Discovery of novel napabucasins bearing sulfonylpiperazine scaffolds as potent STAT3 inhibitors for the treatment of prostate cancer.

Prostate cancer (PCa) is a frequently observed male cancer characterized by high morbidity and mortality. STAT3 is closely related to the occurrence and development of cancer, suggesting that it may be an antitumor therapeutic target. In this study, we prepared various napabucasins bearing sulfonylpiperazine scaffolds as STAT3 inhibitors to treat PCa. Among these compounds, YN11 was the most potent, with an IC50 value of 23 nM in DU145 cells, which is 8.8 times greater than the IC50 value of napabucasin. Mechanistic studies revealed that YN11 directly binds to the STAT3 SH2 domain, inhibiting the phosphorylation of STAT3 while reducing the expression of downstream target proteins. Moreover, YN11 triggered cell cycle arrest, promoted apoptosis, and effectively suppressed PCa cell invasion and migration. In vivo studies revealed that YN11 significantly inhibited tumor growth without inducing considerable weight loss or apparent histopathological alterations in major organs. Our findings indicate that YN11 is a potent STAT3 inhibitor for treating PCa.