The zinc finger domains of PARP-1 are selectively and potently inhibited by the Au(I)-based drugs sodium aurothiomalate and aurothioglucose.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a multidomain enzyme essential for the DNA damage response; its inhibition can lead to cancer cell death. Recruitment of PARP-1 to sites of genomic damage is mediated by its zinc finger domains. In this study, we investigated the inhibition of PARP-1's DNA-dependent activation by three Au(I)-based drugs, presumable zinc-ejectors. We found that aurothioglucose and sodium aurothiomalate selectively inhibited PARP-1's DNA-dependent activity, with IC50 values in the nanomolar range, while preserving its DNA-independent activity. Furthermore, in a BRCA-mutated cell line, both compounds effectively suppressed DNA replication, with half-maximal effective concentrations (EC50) also in the nanomolar range. These findings highlight the potential of selective, zinc finger-targeting PARP-1 inhibitors as promising candidates for anticancer drug testing. Impact statement The need to preserve basal poly(ADP-ribose) polymerase-1 (PARP-1) activity in healthy cells, along with the search for alternative anticancer therapies in cases of drug resistance, led to the discovery of selective and potent zinc finger-targeting inhibitors of PARP-1. This finding opens new opportunities for anticancer drug development.