Molecular Glue Degraders: Ubiquitination Mediated Next-Generation Therapies


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 mechanisms2, 3. This newsletter will delve into MGDs and emerging targets and therapies.


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