PROTAC Compatibilities, Degrading Cell-Surface Receptors, and the Sticky Problem of Finding a Molecular Glue

Graphical Abstract

More generally destructive agents are required to artificially induce cells to use their biochemical machinery for selective protein degradation. Advances include new troubleshooting methods to expose weaknesses in the approach, targeted delivery of inducing agents, special provisions for cell-surface receptors that resist degradation using standard approaches, and manipulation of protein–protein interactions (PPIs) using “molecular glues”.

Abstract

PROteolysis TArgeting Chimeras (PROTACs) are emerging as critical tools in biomedicinal chemistry and drug design, but they have limitations. These limitations include a lack of guiding principles when selecting suitable E3 ligases to induce ubiquitinylation, and problems degrading cell-surface receptors. This Highlight outlines some recent advances that circumvent some of these limitations, and new alternative methods to induce selective protein degradation.