Insights and Future Perspectives of Covalent Protein Degraders

Small-molecule-induced protein degradation has emerged as a compelling approach for targeted elimination of proteins from cells or extracellular space by directing these proteins to the ubiquitin-proteasome or lysosome machinery. Several drugs in the market or currently in clinical trials operate by this mechanism. To date, the majority of the research interests in this field have been focused on small molecules that function through non-covalent interactions in biological system. Protein degraders that leverage covalent chemistry have the potential to expand the scope of both substrate proteins and E3 ubiquitin ligases. In this chapter, we review the recent progress in covalent protein degraders and technologies that facilitate covalent ligand discovery.