Drug Target Strategies
Targeted protein degradation is emerging as a novel strategy for drug discovery. In this modality, bifunctional small molecules are used to redirect specific proteins to the ubiquitin proteasome system where they can be broken down and eliminated from the cell. These bifunctional molecules link together two ligands, one that binds to a target protein and another that binds to an E3 ligase such that these proteins can be drawn into proximity to allow ubiquitylation and ultimately degradation of the protein of interest. Removal of proteins from cells or tissues as opposed to direct inhibition of function may afford a differentiated therapeutic profile and could offer particular value when eliminating pathological proteins from disease states like cancer. Furthermore, this approach may broaden the spectrum of proteins amenable to small molecule therapy owing to the fact that the target ligand needs only to bind to the protein surface, presumably a less challenging hurdle for discovery. This presentation will describe Nurix’s approach to the discovery and evaluation of bifunctional degraders and will discuss our emphasis on novel ligand discovery. Specifically, this talk with highlight our use of DNA-encoded library technology to better enable identification of degradation-compatible ligands across a range of protein targets and E3 ubiquitin ligases.