G protein-coupled receptors (GPCRs) are frequently targeted in the clinic by small molecule antagonists to inhibit specific signalling processes in disease. While this approach has been very successful, newer pharmacological modalities may target GPCRs more effectively, potentially generating improved therapeutics for the treatment of many diseases. In recent years, methods have been developed to exploit the ubiquitin-proteasome system to artificially degrade target proteins. While targeted protein degraders have potential as novel therapeutics and as biological tools for discovery research, targeted degradation of GPCR has remained challenging.1
We have investigated the degradation of different GPCRs using the FKBP12F36V dTAG fusion system.2 Additional studies were performed on the β2-adrenoceptor (β2AR), as suppressing its signalling action leads to more favourable outcomes in triple negative breast cancer.3 Our dTAG fusion experiments demonstrated more effective degradation when targeting the von Hippel-Lindau enzyme compared to cereblon. To determine whether the un-tagged β2AR could also be degraded, we designed genetically encoded nanobody-based degraders and PROteolysis TArgeting Chimeras (PROTACs). These experiments validate that the β2AR is amenable to targeted protein degradation technology. Ultimately, these studies are the first steps towards developing targeted degradation tools and PROTACs for the β2AR and other GPCRs. Our studies will help pave the way for the development of novel GPCR degrader tools.