Hypoxia-Targeted Protein-Targeting Chimeras (htPROTACS)
Stuart Conway (external)
Protein-targeting chimeras (PROTACS) are bifunctional molecules that hijack the cellular machinery for protein degradation, via the ubiquitination pathway, to target the degradation of a defined target protein. These molecules comprise a ligand for an E3 ubiquitin ligases linked to a ligand for the target protein. There have been reports of PROTACS that give targeted degradation of a wide range of proteins, and this technology is now the focus of intense interest in drug discovery. Despite this, there are a number of questions that remain regarding the clinical application of PROTACS, in particular whether the protein degradation can be sufficiently localised to diseased cells and tissue, over healthy cells and tissues. In this project we will develop PROTACS that are targeted to hypoxia, regions of low oxygen, which are characteristic of tumours (htPROTACS). These htPROTACS will allow protein degradation only in regions of hypoxia, meaning that the target protein will be degraded selectively in tumours, sparing the protein in healthy cells.