Molecular Glue Degraders: Ubiquitination Mediated Next-Generation Therapies

Introduction

Targeted protein degradation is an emerging drug discovery strategy that uses small molecules to target disease-causing proteins for degradation mainly via the ubiquitin–proteasome (UPS) pathway.  The promise of these drugs over classical small molecule inhibitors is their potential to target “non-druggable” targets, overcome drug resistance, and produce a higher activity or range of action; thus, drugs that target protein degradation are emerging as novel therapeutic approaches in a wide range of diseases including inflammatory disorders, cancers, neurodegenerative diseases, and others^{(reviewed in 1)}. The two prototypical drugs that induce protein degradation include proteolysis-targeting chimera (PROTACs) and molecular glue degraders (MGDs) both of which have shown tremendous promise at targeting aberrant proteins for degradation (see Figure 1). MGDs a class of small molecules that induce, stabilize, or enhance protein-protein interactions between key regulatory proteins and ubiquitin ligases, have exploded in popularity since the identification that the immunomodulatory drug, thalidomide, functions through targeted protein degradation mechanisms^{2, 3}. This newsletter will delve into MGDs and emerging targets and therapies.