Work

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

Year: 2025

Type: article

Abstract: 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 IC 50 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 (EC 50 ) 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.

Source: FEBS Letters

DOI: 10.1002/1873-3468.70224

Authors: Uliana Bashtanova, Melinda Jane Duer

Institution: University of Cambridge

Language: English

Topic: PARP inhibition in cancer therapy

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,980