Structural Optimization and Characterization of Highly Potent and Selective STAT3 Inhibitors for the Treatment of Triple Negative Breast Cancer

Abstract

Effective targeted treatments for triple-negative breast cancer (TNBC), which has the worst prognosis among various types of breast cancer, are lacking owing to its clinical heterogeneity and malignant nature. STAT3, a key transcription factor, regulates multiple physiological functions. Aberrant activation of STAT3 plays a pivotal role in the initiation and progression of TNBC and is closely associated with a poor prognosis. Therefore, targeting STAT3 is a promising potential therapeutic approach for TNBC. In this study, we further optimized the core structure of 6f, which our research group previously identified as a STAT3 inhibitor and treatment for osteosarcoma, to identify additional potential STAT3 inhibitors for TNBC treatment. We identified WR-S-462 as a high-binding affinity inhibitor of STAT3 that effectively suppresses its phosphorylation and biological functions in vitro. Notably, WR-S-462 significantly inhibits TNBC growth and metastasis in a dose-dependent manner, providing robust evidence for its potential as a clinical intervention for TNBC.