摘要
The recent report by Slabicki et al.in Nature used an array of techniques including cryo-electron microscopy to elucidate the mechanism of action of BI-3802,a molecular glue.1 The discovery of small molecules that highjack cellular quality control machinery to selectively degrade proteins has generated considerable excitement in the drug discovery community,particularly toward targets often deemed"undruggable".Whether its proteolysis targeting chimeras(PROTACs),consisting of heterobifunctional molecules connected by a linker that facilitates the recruitment of an E3 ligase to the protein of interest(POI)or small molecules that function as molecular glues2 to induce a novel interaction between an E3 ligase and the POI,the ultimate goal is to tag the POI for destruction in cells.PROTAC design is relatively straight forward,wherein a POI binding small molecule,and an E3 ligase binding ligand are connected through a linker that enables stable ternary complex formation(POI:PROTAC:E3 ligase)followed by POI degradation.
