Fully G protein-biased GPR183 agonist TUG-2604 reaches oxysterol-like efficacy
- SAR optimization of earlier virtual-screening hits, themselves derived from the antagonist NIBR189, gave full GPR183 agonists with complete G protein bias.
- The lead, TUG-2604, matches the endogenous oxysterol 7α,25-OHC in potency and efficacy without recruiting β-arrestin2.
- It failed to drive human dendritic cell migration on its own and blocked migration induced by the oxysterol.
💡 Points
Turning an antagonist-derived hit into a full agonist with complete G protein bias is not routine, and the migration data hint that β-arrestin signaling carries the chemotaxis. For anyone weighing GPR183 in inflammation, this is a clean tool to separate the two arms before committing to a direction.
Development of Potent G Protein Pathway-Biased GPR183 Agonists ↗