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. 2025 Mar 13;68(5):5687-5698.
doi: 10.1021/acs.jmedchem.4c02952. Epub 2025 Feb 20.

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

Sailajah Gukathasan  1 , Chibuzor Olelewe  1 , Libby Ratliff  1 , Jong H Kim  1 , Alyson M Ackerman  1 , J Robert McCorkle  2 , Sean Parkin  1 , Gunnar F Kwakye  3 , Jill M Kolesar  2   4 , Samuel G Awuah  1   2   4   5
Affiliations

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

Sailajah Gukathasan et al. J Med Chem. .

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.

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Conflict of interest statement

Conflict of Interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare the following competing financial interest(s): S.G.A. has patents pending to University of Kentucky Research Foundation. S. G.A. serves on the advisory board and is Chief Executive Officer of Ayarissa Biosciences.

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