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Interfering with Metabolic Profile of Triple‐Negative Breast Cancers Using Rationally Designed Metformin Prodrugs
Author(s) -
Babak Maria V.,
Chong Kai Ren,
Rapta Peter,
Zannikou Markella,
Tang Hui Min,
Reichert Lisa,
Chang Meng Rui,
Kushnarev Vladimir,
Heffeter Petra,
MeierMenches Samuel M.,
Lim Zhi Chiaw,
Yap Jian Yu,
Casini Angela,
Balyasnikova Irina V.,
Ang Wee Han
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202102266
Subject(s) - metformin , phenformin , prodrug , triple negative breast cancer , breast cancer , medicine , cancer research , cytotoxic t cell , metastatic breast cancer , pharmacology , cancer , oncology , chemistry , in vitro , insulin , biochemistry
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 Au III 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 Au III 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.