Interfering with Metabolic Profile of Triple‐Negative Breast Cancers Using Rationally Designed Metformin Prodrugs

Triple‐negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates. We designed a series of novel AuIII cyclometalated prodrugs of energy‐disrupting Type II antidiabetic drugs namely, metformin and phenformin. Prodrug activation and release of the metformin ligand was achieved by tuning the cyclometalated AuIII fragment. The lead complex 3met was 6000‐fold more cytotoxic compared to uncoordinated metformin and significantly reduced tumor burden in mice with aggressive breast cancers with lymphocytic infiltration into tumor tissues. These effects was ascribed to 3met interfering with energy production in TNBCs and inhibiting associated pro‐survival responses to induce deadly metabolic catastrophe. AuIII prodrugs of anti‐diabetic medicines metformin and phenformin were developed. These compounds effectively decreased triple negative breast tumor burden. The mode of action of novel complexes was linked to energetic crisis and abolishment of pro‐survival responses leading to irreversible cell death.