What Lies Beyond TXNRD1? Cyclometallated Gold Compounds Reveal Sec Selectivity in Glutathione Peroxidases

The selenoenzyme GPX4 is a central regulator of ferroptosis, a form of cell death driven by lipid peroxidation, yet selective inhibitors remain scarce. Here, we present a series of cyclometallated gold(III) compounds and explore their ability to promote C-Se coupling under biocompatible conditions. Competitive reactions with selenium- and sulfur-containing substrates revealed a clear preference for selenium, confirmed in selenopeptide models mimicking the GPx active site. The six-membered metallacycles potently inhibited GPx1, while in vitro GPx4 inhibition was less pronounced. LC-MS identified selenocysteine (Sec51) as the primary arylation site on GPx1. Finally, this chemoselectivity translated to an intracellular setting: in A375 GPx4 WT versus U46C mutant cell lines, viability assays showed a modest IC₅₀ decrease for WT cells, and a six-day proliferation assay revealed a marked effect in WT cells relative to the mutant.