Implications of frequent hitter E3 ligases in targeted protein degradation screens

Targeted protein degradation (TPD) offers a promising approach for chemical probe and drug discovery that uses small molecules or biologics to direct proteins to the cellular machinery for destruction. Among the >600 human E3 ligases, CRBN and VHL have served as workhorses for ubiquitin–proteasome system-dependent TPD. Identification of additional E3 ligases capable of supporting TPD would unlock the full potential of this mechanism for both research and pharmaceutical applications. This perspective discusses recent strategies to expand the scope of TPD and the surprising convergence of these diverse screening efforts on a handful of E3 ligases, specifically DCAF16, DCAF11 and FBXO22. We speculate that a combination of properties, including superficial ligandability, potential for promiscuous substrate interactions and high occupancy in Cullin–RING complexes, may position these E3 ligases as ‘low-hanging fruit’ in TPD screens. We also discuss complementary approaches that might further expand the E3 ligase landscape supporting TPD. This Perspective discusses recent strategies to expand the scope of targeted protein degradation (TPD) and the implications of unexpected convergence of diverse screening efforts on a small subset of TPD-competent E3 ligases in the human proteome.