PROTACs (PROteolysis TArgeting Chimeras) are heterobifunctional molecules with a distinct ligand that targets a specific E3 ligase which is tethered by another ligand specific for the target protein, using an optimized chemical linker.

Current PROTAC discovery heavily relies on monitoring the Ternary complex formation using biophysical and biochemical approaches like TR-FRET proximity ligand assays and SPR that does not monitor true function of PROTAC i.e., PROTAC-mediated ubiquitination.

Designing PROTACs that harness the protein’s intrinsic properties, such as exposed lysines that in turn result in efficient ubiquitination, is crucial to develop potent degraders. Most current PROTACs utilize only a few E3 ligases, which ultimately hinders the vast expansion of the undruggable proteasome.