Anti-cancer binuclear gold(I) complexes with mixed bis(N-heterocyclic carbene) and bis(diphenylphosphino)carborane ligands inhibit thioredoxin reductase and engage ubiquitin-conjugating enzyme E2 C UBE2C in lung cancer cells

This article reports on the anti-cancer properties of a series of binuclear gold(I) complexes containing mixed bis(diphenylphosphine)carborane and bis(N-heterocyclic carbene) bridging ligands. Among them, the most active complex, 1b, is stable to serum thiols (such as glutathione and serum albumin), exhibits cytotoxicity against cancer cells, inhibits thioredoxin reductase activity, and effectively suppresses tumor growth in two mouse models. Complex 1b was also found to inhibit angiogenesis in cell culture and tumor models. We used unbiased thermal proteosome profiling to identify the molecular targets of 1b. The results showed that the ubiquitin-conjugating enzyme E2 C UBE2C, an oncogenic protein highly expressed in a number of cancers, interacts with 1b, and this result was further validated by cellular thermal shift assays and biolayer interferometry assays.