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

In this work, we discovered a novel organometallic gold(III) macrocycle, <b>Au-Mac1,</b> 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 <b>Au-Mac1</b> engages HMOX2 in cells. Downstream effects of <b>Au-Mac1</b> on the depletion of mitochondrial membrane proteins and bioenergetics point to the potential role of HMOX2 in cancer. Importantly, <b>Au-Mac1</b> 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, <b>Au-Mac1</b> is the first gold complex that targets HMOX2 to elicit an anticancer effect.