Ligand-induced genetic degradation as a tool for target validation

Abstract

Targeted protein degraders, known as proteolysis targeting chimeras (PROTACs), are drawing more attention as next-generation drugs to target currently undruggable proteins. As drug discovery of functional degraders involves time- and cost-consuming laborious processes, we propose employing a ligand-induced genetic degradation system to validate candidate proteins before degrader development. Genetic degradation mimics degrader treatment by depleting a degron-fused protein in the presence of a defined ligand. All genetic systems use a combination of a degron and defined ligand that enables a protein of interest fused with the degron to be recruited to an E3 ubiquitin ligase for ubiquitylation and subsequent degradation by the proteasome. However, these events are based on different principles and have different features. We review the dTAG, HaloTag-based, auxin-inducible degron (AID), and destabilizing domain (DD) systems and discuss a strategy for degrader discovery against novel target proteins.