Abstract
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.
Original language | English (US) |
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Pages (from-to) | 13405-13413 |
Number of pages | 9 |
Journal | Angewandte Chemie - International Edition |
Volume | 60 |
Issue number | 24 |
DOIs | |
State | Published - Jun 7 2021 |
Funding
The work described in this paper was funded by Ministry of Education Singapore (MOE2018-T2-1-139 to W.H.A.). M.V.B. acknowledges financial support from City University of Hong Kong (Project No. 7200682 and 9610518). I.V.B. acknowledges support from the Lynn Sage Cancer Research Foundation. M.V.B. acknowledges Tibor Hajsz for generating the artworks and Siti Nuraisyah Bte Nordin for help with Seahorse experiments. A.C. acknowledges Cardiff University for funding. This work was also supported by the Northwestern University the Center for Advanced Microscopy and the Mouse Histology and Phenotyping Laboratory supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. P.R. acknowledges financial support from Slovak Grant Agencies APVV (grant APVV-19-0024) and VEGA (grant 0504/20). The work described in this paper was funded by Ministry of Education Singapore (MOE2018‐T2‐1‐139 to W.H.A.). M.V.B. acknowledges financial support from City University of Hong Kong (Project No. 7200682 and 9610518). I.V.B. acknowledges support from the Lynn Sage Cancer Research Foundation. M.V.B. acknowledges Tibor Hajsz for generating the artworks and Siti Nuraisyah Bte Nordin for help with Seahorse experiments. A.C. acknowledges Cardiff University for funding. This work was also supported by the Northwestern University the Center for Advanced Microscopy and the Mouse Histology and Phenotyping Laboratory supported by NCI P30‐CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. P.R. acknowledges financial support from Slovak Grant Agencies APVV (grant APVV‐19‐0024) and VEGA (grant 0504/20).
Keywords
- antitumor agents
- drug discovery
- metabolism
- metformin
- prodrugs
ASJC Scopus subject areas
- General Chemistry
- Catalysis
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CCDC 1939306: Experimental Crystal Structure Determination
Babak, M. V. (Contributor), Chong, K. R. (Contributor), Rapta, P. (Contributor), Zannikou, M. (Contributor), Tang, H. M. (Contributor), Reichert, L. (Contributor), Chang, M. R. (Contributor), Kushnarev, V. (Contributor), Heffeter, P. (Contributor), Meier-Menches, S. M. (Contributor), Lim, Z. C. (Contributor), Yap, J. Y. (Contributor), Casini, A. (Contributor), Balyasnikova, I. V. (Contributor) & Ang, W. H. (Contributor), Cambridge Crystallographic Data Centre, 2022
DOI: 10.5517/ccdc.csd.cc23308j, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccdc.csd.cc23308j&sid=DataCite
Dataset
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CCDC 1939307: Experimental Crystal Structure Determination
Babak, M. V. (Contributor), Chong, K. R. (Contributor), Rapta, P. (Contributor), Zannikou, M. (Contributor), Tang, H. M. (Contributor), Reichert, L. (Contributor), Chang, M. R. (Contributor), Kushnarev, V. (Contributor), Heffeter, P. (Contributor), Meier-Menches, S. M. (Contributor), Lim, Z. C. (Contributor), Yap, J. Y. (Contributor), Casini, A. (Contributor), Balyasnikova, I. V. (Contributor) & Ang, W. H. (Contributor), Cambridge Crystallographic Data Centre, 2022
DOI: 10.5517/ccdc.csd.cc23309k, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccdc.csd.cc23309k&sid=DataCite
Dataset