biostudies-literatureBelcher BPMark Foundation For Cancer ResearchNCI NIH HHSNovartis Institutes for BioMedical ResearchNovartis-Berkeley Center for Proteomics and Chemistry TechnologiesNomura Research Group588-600https://www.ebi.ac.uk/biostudies/studies/S-EPMC8928483biostudies-literatureUnknown62(3)Targeted protein degradation (TPD) using proteolysis targeting chimeras (PROTACs) and molecular glue degraders has arisen as a powerful therapeutic modality for eliminating disease-causing proteins from cells. PROTACs and molecular glue degraders employ heterobifunctional or monovalent small molecules, respectively, to chemically induce the proximity of target proteins with E3 ubiquitin ligases to ubiquitinate and degrade specific proteins via the proteasome. Whereas TPD is an attractive therapeutic strategy for expanding the druggable proteome, only a relatively small number of E3 ligases out of the >600 E3 ligases encoded by the human genome have been exploited by small molecules for TPD applications. Here we review the existing E3 ligases that have thus far been successfully exploited fBiochemistryLigandability of E3 Ligases for Targeted Protein Degradation Applications.PMC8928483R01 CA240981R35 CA263814Belcher BPNomura DKWard CCfalseLigandability of E3 Ligases for Targeted Protein Degradation Applications.Targeted protein degradation (TPD) using proteolysis targeting chimeras (PROTACs) and molecular glue degraders has arisen as a powerful therapeutic modality for eliminating disease-causing proteins from cells. PROTACs and molecular glue degraders employ heterobifunctional or monovalent small molecules, respectively, to chemically induce the proximity of target proteins with E3 ubiquitin ligases to ubiquitinate and degrade specific proteins via the proteasome. Whereas TPD is an attractive therapeutic strategy for expanding the druggable proteome, only a relatively small number of E3 ligases out of the >600 E3 ligases encoded by the human genome have been exploited by small molecules for TPD applications. Here we review the existing E3 ligases that have thus far been successfully exploited f2023-01-01T00:00:00Z2023 Feb2026-05-09T22:28:11.25Z2025-04-25T17:05:57.9ZS-EPMC89284833447392410.1021/acs.biochem.1c00464