MICRO-TAG® cell target engagement redefines GPCR drug discovery with functional relevance

G protein-coupled receptors (GPCRs) form the largest and most pharmacologically important family of membrane proteins, translating extracellular cues into intracellular signaling cascades. As master regulators of cell metabolism, differentiation, growth, neurotransmission, and sensory perception, GPCRs remain among the most valuable yet technically challenging therapeutic targets. Discovery of drugs targeting these receptors is a challenge in early drug discovery. Conventional biophysical methods that rely on recombinant or purified proteins have achieved limited success, as they poorly capture the structural and functional relevance of GPCRs outside of their native cellular context. Here, we present the MICRO-TAG ® Cell Target Engagement platform as a cellular and translatable assay system capable of identifying and functionally validating compounds that directly bind GPCRs in their native membrane environment. Using GPR75 - a receptor implicated in obesity, cancer, and metabolic syndrome-as a model, we demonstrate the ability of MICRO-TAG ® to: (1) detect direct ligand-receptor binding, (2) monitor downstream GPCR signaling, and (3) provide sensitive reporter-based readouts of agonist or antagonist activity. By integrating direct target engagement with functional pathway interrogation in a cellular environment, MICRO-TAG ® enables scalable and physiologically relevant drug discovery for some of the most challenging drug target classes in biology.