Remarkable advances have been made in cancer targeted therapies with small molecule inhibitors and monoclonal antibodies. Drug resistance and off-target effects have limited their use making researchers seek more effective targeted therapies. With the development of PROteolysis TArgeting Chimeras (PROTACs), the utilization of protein degradation mechanisms as a therapeutic strategy to degrade oncogenic proteins is undergoing revolutionary advances. PROTACs, heterobifunctional structures consist of ligands that bind the protein to be degraded and ligands to E3 ubiquitin ligases giving them unique approaches to the protein degrader field.

The first oral PROTACs (ARV-110 and ARV-471) have shown encouraging results in clinical trials with prostate and breast cancer patients. These promising initial drug candidates have sparked greater enthusiasm for developing the next generation of PROTACs. 

PROTAC-mediated bridging between the protein of interest and E3 ligase promotes protein ubiquitination and its proteasomal degradation. There is a greater emphasis and need to optimize the ligases used in the design of PROTACs for specific tumor tissues to develop targeted therapeutics.