Molecular Glue Degraders and the Expanding Design Space of Drug Discovery

Medicinal Chemistry and Chemical Biology Highlights

Abstract

Small-molecule drug discovery has long centered on inhibiting protein function through high-affinity binding to defined active sites. An emerging alternative shifts the focus from inhibition to rewiring - modulating protein-protein interactions within cellular networks to alter protein fate. Targeted protein degradation is a direct expression of this priniciple: small molecules facilitate interactions that enable ubiquitination and elimination of the target itself. Molecular glue degraders exemplify this strategy. Rather than relying on bifunctional tethering or sustained target occupancy, they reshape recognition within the ubiquitin–proteasome system, stabilising productive interfaces between target proteins and E3 ligases to induce selective degradation. In doing so, they access layers of cellular regulation that conventional pharmacological approaches cannot readily engage. Yet, molecular glue activity has proven challenging to engineer or identify prospectively. This column examines why and argues that realising their broader potential will require more than scale alone: it will depend on integrating chemically biased entry points with a deeper understanding of both how the ubiquitin–proteasome system recognises substrates and which interface chemistries are most amenable to rewiring.