Oral Presentation 21st International Conference on Biological Inorganic Chemistry 2025

The development of Pt-PROTACs to degrade Pt(II) binding proteins (122588)

Paul O'Dowd 1 , Karina Chan 1 , Joshua McLean 1 , Keelan Farnan 1 , Triona Ní Chonghaile 1 , Darren M Griffith 1
  1. Royal College Of Surgeons In Ireland, Dublin, CO. DUBLIN, Ireland

Proteolysis targeting chimeras (PROTACs) have emerged as a technology that can efficiently degrade target proteins. PROTACs are bifunctional molecules that hijack the ubiquitin proteasome system (UPS) to achieve degradation of proteins of interest (POIs) such as disease-related target proteins. Significantly the selective degradation of a broad spectrum of protein targets from transcription factors to enzymes has been reported. PROTACs consist of a ligand that binds to an E3 ligase, connected by an appropriately designed linker to a second ligand that binds to particular POIs. We recently reported the development of the first metallo-PROTAC, specifically a Pt-PROTAC, that can effectively degrade select Pt(II)-binding proteins. This novel Pt-PROTAC consists of an E3 ligase ligand connected by a linker to a Pt(II) centre via a stable amine carrier ligand and where the Pt(II) centre acts as a protein targeting warhead. Protein binding by this Pt-PROTAC will therefore instigate the formation of a ternary complex, PtBindingProtein-PtPROTAC-E3 ligase, and recruit E3 ligases to the vicinity of the PtBindingProtein, promoting ubiquitination and subsequent degradation by the proteasome through proteolysis. Our Pt-PROTAC prototype successfully degraded thioredoxin-1 and thioredoxin reductase-1 in multiple myeloma cancer cell lines.1 Furthermore the design and synthesis of a novel series of Pt-PROTACs will be described together with data concerning protein degradation activity and cell death analysis. Metallo-PROTACs may have important applications in the identification of metal binding proteins and as chemotherapeutic agents.

  1. (1) P. D. O’Dowd, G. P. Sullivan, D. A. Rodrigues, T. N. Chonghaile and D. M. Griffith, Chem. Commun., 2023, 59, 12641-12644.