Emerging strategies for prospective discovery of molecular glue degraders

Abstract

Molecular glue (MG) degraders are monovalent small molecule compounds that co-opt E3 ubiquitin ligases to target neo-substrates for proteasomal degradation. Here, we provide a concise review of recent advances in rational MG discovery, which are categorized into two major strategies, ligand modification and de novo discovery. We also highlight the structural mechanisms underlying the formation of MG-enabled ternary complexes and their thermodynamic properties. Finally, we summarize the broader category of proximity inducers including MGs, proteolysis-targeting chimeras (PROTACs), peptides, and viral proteins. MGs are specified as a unique class of proximity inducers with chemical simplicity and a requirement of pre-existing weak protein-protein interactions. We propose that leveraging the weak basal interaction provides a starting point to prospectively develop MGs to degrade high-value therapeutic targets.