Motso, A.; Pelcman, B.; Kalinovich, A.; Kahlous, N. A.; Bokhari, M. H.; Dehvari, N.; Halleskog, C.; Waara, E.; de Jong, J.; Cheesman, E.; Kallenberg, C.; Yakala, G. K.; Murad, P.; Wetterdal, E.; Andersson, P.; van Beek, S.; Sandström, A.; Alleluia, D. N.; Talamonti, E.; Youhanna, S.; Sabatier, P.; Koenig, C.; Willems, S.; Kemas, A. M.; Hutchinson, D. S.; Ham, S.; Grätz, L.; Voss, J.; Marchan-Alvarez, J. G.; Priede, M.; Jaunsleine, K.; Spura, J.; Kovada, V.; Supe, L.; Stoddart, L. A.; Holliday, N. D.; Newton, P. T.; Pillon, N. J.; Schulte, G.; Summers, R. J.; Mutule, I.; Suna, E.; Olsen, J. V.; Molenaar, P.; Carlsson, J.; Lauschke, V. M.; Wright, S. C.; Bengtsson, T. GRK-Biased Adrenergic Agonists for the Treatment of Type 2 Diabetes and Obesity. Cell 2025, 188 (19), 5142–5156. DOI: 10.1016/j.cell.2025.05.042
Abstract
Biased agonism of G protein-coupled receptors (GPCRs) offers potential for safer medications. Current efforts have explored the balance between G proteins and β-arrestin; however, other transducers like GPCR kinases (GRKs) remain understudied. GRK2 is essential for β2 adrenergic receptor (β2AR)-mediated glucose uptake, but β2AR agonists are considered poor clinical candidates for glycemic management due to Gs/cyclic AMP (cAMP)-induced cardiac side effects and β-arrestin-dependent desensitization. Using ligand-based virtual screening and chemical evolution, we developed pathway-selective agonists of β2AR that prefer GRK coupling. These compounds perform well in preclinical models of hyperglycemia and obesity and demonstrate a lower potential for cardiac and muscular side effects compared with standard β2-receptor agonists and incretin mimetics, respectively. Furthermore, the lead candidate showed favorable pharmacokinetics and was well tolerated in a placebo-controlled clinical trial. GRK-biased β2AR partial agonists are thus promising oral alternatives to injectable incretin mimetics used in the treatment of type 2 diabetes and obesity.