Leading Drug Discovery Scientists Leverage PathHunter® Arrestin Technology for Discovery of Novel GPCR Drugs

Three landmark studies published this year highlight the critical role of ß-Arrestin signaling for novel GPCR drug development. These findings, conducted using the highly validated PathHunter® ß-Arrestin technology, are galvanizing drug discovery programs in their hunt for new targets and better treatments.

Earlier this year, researchers at DiscoveRx Corporation in conjunction with scientists at GlaxoSmithKline and Medical Research Council Technology published a study using the Arrestin platform on an unprecedented scale to identify natural ligands for previously intractable orphan GPCRs. (Southern et al., Journal of Biomolecular Screening,18(5): 599–609, 2013). A second publication with researchers at Bristol Myers Squibb identified the first set of positive allosteric modulators (PAMs) of the µ-Opioid receptor, providing proof-of-concept for an exciting new class of drugs that could have greater therapeutic potential in pain management. (Burford et al., PNAS, 110(26): 10830–10835, 2013).

In a more recent publication with Dr. Sudarshan Rajagopal’s team from Duke University (Rajagopal, et al., JBC, 2013, doi:10.1074/jbc.M113.479113), a combination of Arrestin recruitment, receptor internalization and second messenger assays were utilized to explore the signaling bias of endogenous chemokine ligands. “Classically, different chemokines targeting the same receptor were thought to be biochemically redundant,” said Dr. Rajagopal. “But quantitative comparison of the activation patterns across several chemokine receptors and their ligands demonstrated that these ligands were biochemically distinct, activating intracellular pathways with signatures specific to the ligand-receptor pair.” Dr. Tom Wehrman, Vice President of R&D at DiscoveRx Corporation further added “Although many synthetic GPCR ligands exhibit pathway selective activation patterns, the observation that endogenous ligands also show bias indicates that this phenomenon is more general than once believed. These results further emphasize the importance of measuring receptor activation using multiple read-outs”.

About PathHunter® GPCR Portfolio
DiscoveRx provides an industry leading portfolio of over 600 naturally coupled GPCR assays designed to detect GPCR signaling through second messenger activation, arrestin binding and receptor internalization. By providing access to the same GPCR target in different technology formats, multiple signaling pathways can be assayed in parallel using the same robust, reliable and screening-friendly chemiluminescent format. Over the past 7 years, DiscoveRx’s innovative approach to GPCR drug discovery has enabled novel biased ligand discovery and led to a better understanding of receptor activity and compound mechanism.