Chemoproteomic Profiling of a Carbon-Stabilized Gold(III) Macrocycle Reveals Cellular Engagement with HMOX2

Authors

• Sailajah Gukathasan, University of KentuckyFollow
• Chibuzor Ngozi Olelewe, University of KentuckyFollow
• Libby Ratliff, University of Kentucky
• Jong H. Kim, University of Kentucky
• Alyson M. Ackerman, University of Kentucky
• J. Robert McCorkle, University of KentuckyFollow
• Sean Parkin, University of KentuckyFollow
• Gunnar F. Kwakye, Oberlin College
• Jill M. Kolesar, University of KentuckyFollow
• Samuel G. Awuah, University of KentuckyFollow

Abstract

In this work, we discovered a novel organometallic gold(III) macrocycle, Au-Mac1, that demonstrates anticancer potency in a panel of triple-negative breast cancer cells (TNBC), and based on this complex, a biotinylated-Au-Mac1 probe was designed for target identification via chemoproteomics, which uncovered the engagement of HMOX2 of the heme-energy metabolism pathway. Using orthogonal chemical biology and molecular biology approaches, including immunoblotting, flow cytometry, and cellular thermal shift assays, it was confirmed that Au-Mac1 engages HMOX2 in cells. Downstream effects of Au-Mac1 on the depletion of mitochondrial membrane proteins and bioenergetics point to the potential role of HMOX2 in cancer. Importantly, Au-Mac1 inhibits in vivo tumor growth of metastatic breast tumor-bearing mice. We believe that this approach is clinically relevant in network-oriented drug discovery. To the best of our knowledge, Au-Mac1 is the first gold complex that targets HMOX2 to elicit an anticancer effect.

Document Type

Article

Publication Date

2025

Notes/Citation Information

© 2025 American Chemical Society

Digital Object Identifier (DOI)

https://doi.org/10.1021/acs.jmedchem.4c02952

Funding Information

We are grateful for financial support from the National Cancer Institute (NCI) R01CA258421-01 (S.G.A.) and the UK Igniting research collaboration support (J.K. and S.G.A.). The authors also acknowledge the support of the Center for Pharmaceutical Research and Innovation (NIH P20 GM130456). We would like to thank the following facilities at the University of Kentucky who provided support in the completion of the experiments detailed in this manuscript. The UK NMR Center is supported by NSF (CHE-997738) and the UK X-ray facility is supported by the MRI program from NSF (CHE-1625732). For the flow cytometry experiments, we would like to thank the UK Flow Cytometry and Immune Function Core supported by the Office of the Vice President of Research, the Markey Cancer Center, and the NCI Center Core Support Grant (P30 CA177558). TNBC cells were gifted by Dr. Kathleen O’Connor.

Repository Citation

Gukathasan, Sailajah; Olelewe, Chibuzor Ngozi; Ratliff, Libby; Kim, Jong H.; Ackerman, Alyson M.; McCorkle, J. Robert; Parkin, Sean; Kwakye, Gunnar F.; Kolesar, Jill M.; and Awuah, Samuel G., "Chemoproteomic Profiling of a Carbon-Stabilized Gold(III) Macrocycle Reveals Cellular Engagement with HMOX2" (2025). Chemistry Faculty Publications. 204.
https://uknowledge.uky.edu/chemistry_facpub/204