Chemoproteomic Profiling of a Carbon-Stabilized Gold(III) Macrocycle Reveals Cellular Engagement with HMOX2
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.
Repository Citation
Gukathasan, Sailajah, Chibuzor Olelewe, Libby Ratliff, et al. 2025. "Chemoproteomic Profiling of a Carbon-Stabilized Gold(III) Macrocycle Reveals Cellular Engagement with HMOX2." Journal of Medical Chemistry 68(5): 5687-5698.
Publisher
American Chemical Society
Publication Date
2-1-2025
Publication Title
Journal of Medicinal Chemistry
Department
Neuroscience
Document Type
Article
DOI
https://doi.org/10.1021/acs.jmedchem.4c02952
Keywords
Heme Oxygenase-2, Target, Inhibition, Chemistry, Biology, Iron
Language
English
Format
text
