GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity
Aikaterini Motso, Benjamin Pelcman, Anastasia Kalinovich, Nour Aldin Kahlous, Muhammad Hamza Bokhari, Nodi Dehvari, Carina Halleskog, Erik Rollman Waara, Jasper M. A. de Jong, Elizabeth Cheesman, Christine Kallenberg, Gopala Krishna Yakala, Praerona Murad, Erika Wetterdal, Pia Andersson, Sten van Beek, Anna Sandström, Diane Natacha Alleluia, Emanuela Talamonti, Sonia Youhanna, Pierre Sabatier, Claire Koenig, Sabine Willems, Aurino M. Kemas, Dana S. Hutchinson, Seungmin Ham, Lukas Grätz, Jan Voss, Jose G. Marchan‐Alvarez, Martins Priede, Krista Jaunsleine, Jana Spura, Vadims Kovada, Linda Supe, Leigh A. Stoddart, Nicholas D. Holliday, Phillip T. Newton, Nicolas J. Pillon, Gunnar Schulte, Roger J. Summers, Ilga Mutule, Edgars Sūna, Jesper V. Olsen, Peter Molenaar, Jens Carlsson, Volker M. Lauschke, Shane C. Wright, Tore Bengtsson
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 β 2 adrenergic receptor (β 2 AR)-mediated glucose uptake, but β 2 AR agonists are considered poor clinical candidates for glycemic management due to G s /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 β 2 AR 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 β 2 -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 β 2 AR partial agonists are thus promising oral alternatives to injectable incretin mimetics used in the treatment of type 2 diabetes and obesity.