Chemical biology of noncanonical G protein–coupled receptor signaling: Toward advanced therapeutics

G protein–coupled receptors (GPCRs), the largest family of signaling membrane proteins, are the target of more than 30% of the drugs on the market. Recently, it has become clear that GPCR functions are far more multidimensional than previously thought, with multiple noncanonical aspects coming to light, including biased, oligomeric, and compartmentalized signaling. These additional layers of functional selectivity greatly expand opportunities for advanced therapeutic interventions, but the development of new chemical biology tools is absolutely required to improve our understanding of noncanonical GPCR regulation and pave the way for future drugs. In this opinion, we highlight the most notable examples of chemical and chemogenetic tools addressing new paradigms in GPCR signaling, discuss their promises and limitations, and explore future directions.