A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer

The first small-molecule inhibitor of chemoattractant GPCR OXE-R disrupts signaling downstream of Gβγ but not Gα i/o , providing evidence that signaling bias can occur between Gβγ and Gα subunits within a heterotrimer. Differential targeting of heterotrimeric G protein versus β-arrestin signaling are emerging concepts in G protein–coupled receptor (GPCR) research and drug discovery, and biased engagement by GPCR ligands of either β-arrestin or G protein pathways has been disclosed. Herein we report on a new mechanism of ligand bias to titrate the signaling specificity of a cell-surface GPCR. Using a combination of biomolecular and virtual screening, we identified the small-molecule modulator Gue1654, which inhibits Gβγ but not Gα signaling triggered upon activation of Gα i -βγ by the chemoattractant receptor OXE-R in both recombinant and human primary cells. Gue1654 does not interfere nonspecifically with signaling directly at or downstream of Gβγ. This hitherto unappreciated mechanism of ligand bias at a GPCR highlights both a new paradigm for functional selectivity and a potentially new strategy to develop pathway-specific therapeutics.