Degron tags can trigger rapid and temporally controlled degradation of proteins using small molecules known as molecular glues. These molecular glues induce or stabilize protein interactions between a target protein and a ubiquitin ligase. As research tools, molecular glue complexes are limited by the large size of degron tags, which prevents integration in endogenous protein-coding genes. In a study published in Science, Mercer et al. apply a continuous evolution approach to generate molecular glue complexes with high affinities and smaller size, obtaining a compact degron that triggers protein degradation with no detectable off-target effects.

Recent work developed an optimized molecular glue, PT-179, that binds cereblon to trigger protein degradation. Unlike its predecessors, PT-179 does not degrade off-target proteins, making it an ideal starting block to design molecular glue complexes with improved properties.