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Motso A, Pelcman B, Kalinovich A, Kahlous NA, Bokhari MH, Dehvari N, Halleskog C, Waara E, de Jong J, Cheesman E, Kallenberg C, Yakala GK, Murad P, Wetterdal E, Andersson P, van Beek S, Sandström A, Alleluia DN, Talamonti E, Youhanna S, Sabatier P, Koenig C, Willems S, Kemas AM, Hutchinson DS, Ham S, Grätz L, Voss J, Marchan-Alvarez JG, Priede M, Jaunsleine K, Spura J, Kovada V, Supe L, Stoddart LA, Holliday ND, Newton PT, Pillon NJ, Schulte G, Summers RJ, Mutule I, Suna E, Olsen JV, Molenaar P, Carlsson J, Lauschke VM, Wright SC, Bengtsson T
Cell 188 (19) 5142-5156.e23 [2025-09-18; online 2025-06-23]
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.
PubMed 40555230
DOI 10.1016/j.cell.2025.05.042
Crossref 10.1016/j.cell.2025.05.042
pii: S0092-8674(25)00630-0