Eph-Ephrin Tetramerization Inhibitors Target Bidirectional Signaling to Combat Pain and Addiction

Ephs and Ephrins are a large group of interacting membrane-anchored receptor-ligand molecules that form dimers, tetramers, and tetramer superclusters to become activated and signal upon cell-cell contact. While most noted for bidirectional phosphotyrosine signals in development, Ephs/Ephrins also become overexpressed and participate in chronic pathologies, including EphB1 in pain and EphB2 in fibrosis. We searched for small molecules that disrupt EphB-EphrinB receptor-ligand interactions and discovered a large set of 8-hydroxyquinoline compounds that target tetramer-driven EphB1-EphrinB2 and EphB2-EphrinB2 interactions, with less action toward the more dimer-driven EphB4-EphrinB2 interaction. The compounds are orally available, reduce EphB forward signaling and EphrinB reverse signaling, and act to blunt inflammatory pain and opioid withdrawal. Our data indicates 8-hydroxyquinolines, which are known metal-binding compounds, effectively target the high-affinity circular tetramer structure needed for bidirectional signaling.