Advantages of PROTACs over traditional drugs

Proteolysis Targeting Chimera (PROTAC) can overcome most of the limitations of small molecule inhibitors, and they offer several advantages of the traditional concepts of drug discovery by targeted protein degradation. Their Mode of Action (MoA) suggests that a small molecule just needs a brief interaction with its target protein, leading to the loss of function of the target. After the target protein’s destruction, this small-molecule drug can survive and carry on another cycle of target-protein degradation. This sub-stoichiometric activity is catalytic in nature, avoiding maintaining a high level of drug dosage. Since the POI is totally degraded by the body’s own destructive system, and that the target protein must now be resynthesized after the degradation event, overexpression and accumulation of the target protein can be averted by proteolysis targeting chimera technology, leading to fewer adverse effects. In addition to this, traditional inhibition often fails to address the confirmational changes in proteins due to mutations, thus causing increased drug resistance, which is easily addressed by the PROTAC approach, where the intense-target binding is often not required to the unique MoA. Therefore, this approach also has the potential to target the “undruggable” proteome that limits traditional drugs, as the warhead needs only a slight binding affinity to recruit the protein of interest (POI) rather than high inhibition activity.

Classical drugs generally require high drug concentrations to maintain a level of target occupancy that provides sufficient clinical benefit. However, high drug concentrations are also linked to off-target effects. Since the PROTAC efficacy is not limited by equilibrium occupancy, a reduction in protein levels of more than 90% can be reached at nanomolar concentrations. In addition, they promise a more sustained reduction in downstream signaling and the maintenance of response duration even after washout of the PROTAC. In contrast to a typical interaction of an inhibitor with the target protein where the inhibitor is required to bind to a functional binding site and block a single protein interaction, PROTACs result in a ternary complex in which recognition is crucial, whereas potency is of reduced significance. This makes PROTACs more suitable for ‘difficult’ targets, where the known inhibitors are typically a failure due to weak binding and are unsuitable for further clinical development or for protein-protein interactions.