How to target membrane proteins for degradation: Bringing GPCRs into the TPD fold

We are now in the middle of a so-called "fourth wave" of drug innovation: multispecific medicines aimed at diseases and targets previously thought to be "undruggable"; by inducing proximity between two or more proteins, for example, a target and an effector that do not naturally interact, such modalities have potential far beyond the scope of conventional drugs. In particular, targeted protein degradation (TPD) strategies to destroy disease-associated proteins have emerged as an exciting pipeline in drug discovery. Most efforts are focused on intracellular proteins, whereas membrane proteins have been less thoroughly explored despite the fact that they comprise roughly a quarter of the human proteome with G-protein coupled receptors (GPCRs) notably dysregulated in many diseases. Here, we discuss the opportunities and challenges of developing degraders for membrane proteins with a focus on GPCRs. We provide an overview of different TPD platforms in the context of membrane-tethered targets, and we present recent degradation technologies highlighting their potential application to GPCRs.