Research Progress on Small-molecule Proteolytic Targeting Chimera

Proteolytic-targeting chimera(PROTAC) is a new technology to selectively degrade target proteins via ubiquitin-proteasome system. PROTACs are a class of heterobifunctional molecules, which contain a ligand targeting the protein of interest, a ligand recruiting an E3 ligase and a linker connecting these two ligands. Comapred with traditional inhibitor, they provide several advantages in potency, selectivity and drug resistance. Thus, many promising PROTACs have been developed in the recent two decades, especially small-molecule PROTACs. This review selects 4 common E3 ligases, CRBN, VHL, MDM2 and cIAP1 as representatives, and classifies different target targets. It also summarizes the progress of small-molecule PROTACs based on different E3 ligases while describing the characteristics of these four E3 ligases.