Technology for target protein degrader-dependent interaction

Abstract

Targeted protein degraders (TPDs) have emerged as a novel drug discovery modality that induces protein degradation by promoting drug-dependent interactions between target proteins and E3 ubiquitin ligases. The specificity of TPDs is determined by drug-induced protein-protein interactions (PPIs). In this review, we provide an overview of biochemical PPI analyses based on a wheat germ cell-free protein synthesis system combined with the AlphaScreen assay, as well as cellular and in vivo TPD-dependent interactome analyses using the proximity-dependent biotinylation enzyme AirID. Through representative examples, we highlight the importance of evaluating drug-dependent PPIs for understanding TPD specificity and discuss the significance of these approaches in TPD-based drug discovery.