Proteolysis-targeting chimera (PROTAC) in cancer: design principles and applications on “undruggable” targets

Targeted cancer therapies can enhance in vivo efficacy and decrease side effects by changing the distribution and exposure of specific biomolecules in tissues. Nevertheless, there are many cancer target proteins that cannot be targeted by traditional drugs. Some new technologies and drug design strategies have been applied to overcome these "undruggable" targets, among which the most well-known and classic technology is proteolysis-targeting chimeras (PROTACs). In order to design a better PROTAC structure for targeting "undruggable" targets, we elaborated in detail on the design of protein of interest (POI) ligands, E3 ligase ligands and linkers in PROTAC structures, the predicting of PROTAC ternary complex structures, and the advantages and disadvantages of using carriers in PROTAC delivery systems. In addition, this article also reviews the current research status of PROTAC targeting "undruggable" targets, such as kirsten rat sarcoma (KRAS), epidermal growth factor receptor (EGFR), c-Myc and p53. The challenges faced by PROTACs and the possible solutions were discussed, and the possibility of PROTAC broadening the range of drug therapeutic targets, especially the "undruggable" target, was prospected.