Immunomodulatory drugs (IMiDs), including thalidomide, pomalidomide and lenalidomide, act as molecular glues to induce the ubiquitination and degradation of their target proteins (referred to as neosubstrates) by facilitating their direct interaction with cereblon (CRBN), the substrate receptor of the CRL4CRBN E3 ubiquitin ligase. Some neosubstrates contain a C2H2 zinc finger motif that is responsible for binding to CRBN in the presence of IMiDs. These motifs have been harnessed into degrons to induce the degradation of proteins of interest. However, the broad utility of these degrons is limited by the off-target effects of IMiDs.

To overcome this shortcoming, Mercer, DeCarlo, Burman et al. used phage-assisted continuous evolution (PACE) to evolve a compact zinc finger degron, called SD40, that responds to PT-179, a derivative of pomalidomide with no detected off-target effects. SD40 is a 36-amino-acid peptide. Its small size enables its seamless integration into endogenous proteins using genomic knock-in technologies, such as prime editing. Fusion of SD40 to proteins of interest led to highly specific protein degradation in the presence of PT-179, which was confirmed by proteomic analysis. In addition, the team also evolved another degron, named SD56, which can trigger protein degradation in mouse cells.