Targeted protein degradation and drug discovery

Abstract

Targeted protein degradation attracts attention as a novel modality for drug discovery, as well as for basic research. Various types of degrader molecules have been developed so far, which include proteolysis-targeting chimaeras (PROTACs) and specific and nongenetic IAP-dependent protein erasers (SNIPERs), E3 modulators, hydrophobic tagging molecules, IAP antagonists and deubiquitylase inhibitors. PROTACs and SNIPERs are chimeric degrader molecules consisting of a target ligand linked to another ligand that binds to an E3 ubiquitin ligase. In the cells, they recruit an E3 ligase to the target protein, thereby inducing ubiquitylation and proteasomal degradation of the target protein. Because of their modular structure, novel PROTACs and SNIPERs targeting proteins of your interest can be rationally developed by substituting target ligands. In this article, various compounds capable of inducing protein degradation were overviewed, including SNIPER compounds developed in our laboratory.