Membrane‐Bounded Intracellular E3 Ubiquitin Ligase‐Targeting Chimeras (MembTACs) for Targeted Membrane Protein Degradation

Abstract Targeted protein degradation (TPD) represents a potent therapeutic strategy aimed at dismantling disease‐associated target proteins. PROTAC is the most widely developed technique for intracellular protein degradation, while its degradation ability on membrane proteins has been hindered by the need for complex synthetic processes and limited permeability. In this study, we developed the membrane‐bounded intracellular E3 ubiquitin ligase‐targeting chimeras (MembTACs) that simultaneously recruit intracellular E3 ubiquitin ligase and bind to the desired membrane proteins for targeted degradation of membrane proteins. We demonstrate that the MembTACs can effectively utilize intracellular E3 ubiquitin ligase to degrade the therapeutically relevant membrane proteins of EpCAM and Met via the proteasome pathway. We anticipate that the new platform will expand the range of PROTAC applications and provide a new dimension for targeted membrane protein degradation.