Discovery of a novel napabucasin derivative B16 as a potent STAT3 inhibitor for the treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) remains a clinical challenge due to limited treatment options and drug resistance. Signal transducer and activator of transcription 3 (STAT3) is a promising therapeutic target for TNBC, as its hyperactivation drives tumor progression. Here, we report the design and synthesis of a novel series of isoxazole quinone derivatives targeting the STAT3 SH2 domain. Among these, B16 demonstrated exceptional potency, with IC values of 70 nM against TNBC cell lines (MDA-MB-231 and MDA-MB-468), representing a 10-fold improvement over napabucasin. Mechanistic studies revealed that B16 directly binds to the STAT3 SH2 domain, suppresses STAT3 phosphorylation and nuclear translocation, and inhibits colony formation, migration and invasion of TNBC cells. In vivo, B16 (10 mg/kg) reduced tumor volume by 82 % in a MDA-MB-231 xenograft model, outperforming napabucasin (50 % reduction in tumor volume), with no significant toxicity observed. These findings established B16 as a highly potent STAT3 inhibitor, offering a promising therapeutic strategy for TNBC.