Perspectives on the development of first-in-class protein degraders

Targeted protein degradation is a broad and expanding field aimed at the modulation of protein homeostasis. A focus of this field has been directed toward molecules that hijack the ubiquitin proteasome system with heterobifunctional ligands that recruit a target protein to an E3 ligase to facilitate polyubiquitination and subsequent degradation by the 26S proteasome. Despite the success of these chimeras toward a number of clinically relevant targets, the ultimate breadth and scope of this approach remains uncertain. Here we highlight recent advances in assays and tools available to evaluate targeted protein degradation, including and beyond the study of E3-targeted chimeric ligands. We note several challenges associated with degrader development and discuss various approaches to expanding the protein homeostasis toolbox.