PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional small molecules consisting of an E3 ligase recruiting molecule and a target protein ligand, tethered by chemical linkers. There are more than 600 E3 ligases in the human proteome, but only a few ligases are currently being used for targeted protein degradation, such as Cereblon (CRBN), Von Hippel Lindau (VHL), MDM2, and IAPs.

While CRBN and VHL have shown broad applicability for PROTAC applications, the lack of tractable ligands for novel E3 ligases and the lack of reliable screening methods limit the expansion of PROTACs to new E3 ligases. Despite the great success of traditional drug targets (such as kinases) and “undruggable” targets (such as RAS family proteins), there are still many targets that remain elusive and do not benefit from PROTACs.