Expanding the landscape of E3 ligases for targeted protein degradation

Targeted protein degradation (TPD) is a rapidly developing field in chemical biology and drug discovery. Various TPD modalities have emerged, with proteolysis-targeting chimeras (PROTACs) being the most well-developed at present. In PROTACs, a heterobifunctional molecule is used to recruit an E3 ligase to degrade a protein of therapeutic interest. Most of the PROTAC candidates that have been developed thus far use either CRBN or VHL as the hijacked E3 ligase, which poses several limitations. In order to overcome these limitations and furthermore realize the full potential of TPD as a therapeutic modality, the field will need to unlock additional E3 ligases. This review will therefore present 11 alternative E3 ligases for TPD. It will also describe some of the ongoing platform development that is facilitating the discovery of additional E3 ligases for TPD.