The YAP-TEAD4 inhibitor M511-0965 suppresses triple-negative breast cancer progression by downregulating TGFB2.

Triple-negative breast cancer (TNBC) lacks standard targeted therapies, and chemotherapy is associated with significant side effects and economic burden, highlighting the urgent need to develop novel low-toxicity and low-cost strategies. The Hippo pathway serves as a critical regulator of organ development. Its activation phosphorylates Yes-associated protein (YAP) and transcriptional coactivator TAZ, promoting their cytoplasmic degradation and inhibiting their binding to the nuclear transcription factor TEAD, thereby suppressing downstream gene expression. As the terminal effector of this pathway, TEAD plays an important role in various tumors. In this study, bioinformatics and molecular biology experiments revealed that TEAD4 is highly expressed in TNBC, and its expression level influences the biological functions of TNBC. Thus, TEAD4 represents an important therapeutic target for tumors, underscoring the need to identify safe and low-toxicity TEAD4 small-molecule inhibitors. Structure-based virtual screening has become a key step in drug discovery. Focusing on the crystal structure of the YAP/TEAD4 complex, we employed molecular docking technology for screening and identified a novel small-molecule inhibitor. Molecular biology and cellular functional assays confirmed that this inhibitor acts by targeting the YAP/TEAD4 interaction, thereby exerting antitumor effects. This preclinical study provides new insights and experimental evidence for targeted therapy in TNBC.