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Proteolysis targeting chimera (PROTACs) provide a novel therapeutic approach that is revolutionizing drug discovery. The success of PROTACs largely depends on the combination of their three fragments: E3 ligase ligand, linker and protein of interest (POI)-targeting ligand. We summarize the pivotal significance of the precise combination of the E3 ligase ligand with the POI-recruiting warhead, which is crucial for the successful execution of cellular processes and achieving the desired outcomes. Therefore, the key to selection was the use of at least two ligands recruiting two different ligases. This approach enables a direct comparison of the impacts of the specific ligases on target degradation.
Sobierajski et al. (Wed,) studied this question.