Molecular glue degraders: exciting opportunities for novel drug discovery

ABSTRACTIntroductionMolecular Glue Degraders (MGDs) is aconcept that refers to a class of compounds that facilitate the interactionbetween two proteins or molecules within a cell. These compounds act as bridgethat enhances specific Protein-Protein Interactions (PPIs). Over the pastdecade, this technology has gained attention as a potential strategy to targetproteins that were traditionally considered undruggable using small molecules.AreasCoveredThis review presents the concept of cellular homeostasis and the balancebetween protein synthesis and protein degradation. The concept of proteindegradation is concerned with molecular glues, which form part of the broaderfield of Targeted Protein Degradation (TPD). Next, pharmacochemical strategiesfor the rational design of MGDs are detailed and illustrated by examples ofLigand-Based (LBDD), Structure-Based (SBDD) and Fragment-Based Drug Design(FBDD).Expert opinionExpanding the scope of what can beeffectively targeted in the development of treatments for diseases that areincurable or resistant to conventional therapies offers new therapeutic options.The treatment of microbial infections and neurodegenerative diseases is a majorsocietal challenge, and the discovery of MGDs appears to be a promising avenue.Combining different approaches to discover and exploit a variety of innovativetherapeutic agents will create opportunities to treat diseases that are stillincurable.