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P2073
Profiling for GPCR activation using DiscoveRx PathHunter B-Arrestin Technology
Presenter Justin Mika, DiscoveRx Corp., USA
Additional Authors: Neil Charter, Lakshmi Anantharaman, Theresa Schaub, and Keith R. Olson
The DiscoveRx PathHunter Profiling service utilizes protein-protein interactions with ƒÒ-Arrestin to measure GPCR activation. This technology generates comparable data to traditional receptor binding assays and provides additional information on compound mode of action in a cell-based assay format. It has advantages over cellular second messenger assays such as a common assay format for all GPCRs, no requirement for force-coupling and a simple robust chemiluminescent readout. More than 45 receptor families are currently represented totaling over 100 different GPCRs. In addition to characterized receptors, a number of orphan receptor cell lines have been developed for potential de-orphanization applications. While second messengers are well established measures of GPCR activation, arrestin is a more direct assay readout and offers the ability to detect unique pharmacology, and has been used to correctly identify arrestin-biased ligands. Therefore, arrestin is a complementary technology that can provide important added information about compound function and activity. We will highlight results from compound profiling activities utilizing arrestin, and compare rank order potency of known agonists and antagonists for a variety of receptors. We will also demonstrate the utility of our assay for analysis of inverse agonist, allosteric modulators, partial agonists and weak antagonists, emphasizing the benefits of our generic assay approach for a range of receptors and ligand pharmacologies.