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

Maria V. Babak; Kai Ren Chong; Peter Rapta; Markella Zannikou; Hui Min Tang; Lisa Reichert; Meng Rui Chang; Vladimir Kushnarev; Petra Heffeter; Samuel M. Meier-Menches; Zhi Chiaw Lim; Jian Yu Yap; Angela Casini; Irina V. Balyasnikova; Wee Han Ang

doi:10.1002/anie.202102266

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

Maria V. Babak^*, Kai Ren Chong, Peter Rapta, Markella Zannikou, Hui Min Tang, Lisa Reichert, Meng Rui Chang, Vladimir Kushnarev, Petra Heffeter, Samuel M. Meier-Menches, Zhi Chiaw Lim, Jian Yu Yap, Angela Casini, Irina V. Balyasnikova, Wee Han Ang^*

^*Corresponding author for this work

Neurological Surgery

Research output: Contribution to journal › Article › peer-review

57 Scopus citations

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 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.

Original language	English (US)
Pages (from-to)	13405-13413
Number of pages	9
Journal	Angewandte Chemie - International Edition
Volume	60
Issue number	24
DOIs	https://doi.org/10.1002/anie.202102266
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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1002/anie.202102266

Cite this

Babak, M. V., Chong, K. R., Rapta, P., Zannikou, M., Tang, H. M., Reichert, L., Chang, M. R., Kushnarev, V., Heffeter, P., Meier-Menches, S. M., Lim, Z. C., Yap, J. Y., Casini, A., Balyasnikova, I. V., & Ang, W. H. (2021). Interfering with Metabolic Profile of Triple-Negative Breast Cancers Using Rationally Designed Metformin Prodrugs. Angewandte Chemie - International Edition, 60(24), 13405-13413. https://doi.org/10.1002/anie.202102266

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title = "Interfering with Metabolic Profile of Triple-Negative Breast Cancers Using Rationally Designed Metformin Prodrugs",

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.",

keywords = "antitumor agents, drug discovery, metabolism, metformin, prodrugs",

author = "Babak, {Maria V.} and Chong, {Kai Ren} and Peter Rapta and Markella Zannikou and Tang, {Hui Min} and Lisa Reichert and Chang, {Meng Rui} and Vladimir Kushnarev and Petra Heffeter and Meier-Menches, {Samuel M.} and Lim, {Zhi Chiaw} and Yap, {Jian Yu} and Angela Casini and Balyasnikova, {Irina V.} and Ang, {Wee Han}",

note = "Funding Information: 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). Funding Information: 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). Publisher Copyright: {\textcopyright} 2021 Wiley-VCH GmbH",

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Babak, MV, Chong, KR, Rapta, P, Zannikou, M, Tang, HM, Reichert, L, Chang, MR, Kushnarev, V, Heffeter, P, Meier-Menches, SM, Lim, ZC, Yap, JY, Casini, A, Balyasnikova, IV & Ang, WH 2021, 'Interfering with Metabolic Profile of Triple-Negative Breast Cancers Using Rationally Designed Metformin Prodrugs', Angewandte Chemie - International Edition, vol. 60, no. 24, pp. 13405-13413. https://doi.org/10.1002/anie.202102266

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AU - Babak, Maria V.

AU - Chong, Kai Ren

AU - Rapta, Peter

AU - Zannikou, Markella

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N1 - Funding Information: 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). Funding Information: 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). Publisher Copyright: © 2021 Wiley-VCH GmbH

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AB - 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.

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KW - drug discovery

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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CCDC 1939306: Experimental Crystal Structure Determination

CCDC 1939307: Experimental Crystal Structure Determination

Cite this

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Datasets

CCDC 1939306: Experimental Crystal Structure Determination

CCDC 1939307: Experimental Crystal Structure Determination

Cite this