GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity

  • Cell. 2025 Jun 23:S0092-8674(25)00630-0. doi: 10.1016/j.cell.2025.05.042.
Aikaterini Motso  1 ,  Benjamin Pelcman  2 ,  Anastasia Kalinovich  2 ,  Nour Aldin Kahlous  3 ,  Muhammad Hamza Bokhari  4 ,  Nodi Dehvari  2 ,  Carina Halleskog  2 ,  Erik Waara  2 ,  Jasper de Jong  2 ,  Elizabeth Cheesman  5 ,  Christine Kallenberg  2 ,  Gopala Krishna Yakala  2 ,  Praerona Murad  2 ,  Erika Wetterdal  2 ,  Pia Andersson  2 ,  Sten van Beek  2 ,  Anna Sandström  2 ,  Diane Natacha Alleluia  2 ,  Emanuela Talamonti  2 ,  Sonia Youhanna  6 ,  Pierre Sabatier  7 ,  Claire Koenig  8 ,  Sabine Willems  6 ,  Aurino M Kemas  6 ,  Dana S Hutchinson  9 ,  Seungmin Ham  9 ,  Lukas Grätz  10 ,  Jan Voss  10 ,  Jose G Marchan-Alvarez  11 ,  Martins Priede  12 ,  Krista Jaunsleine  12 ,  Jana Spura  12 ,  Vadims Kovada  12 ,  Linda Supe  12 ,  Leigh A Stoddart  13 ,  Nicholas D Holliday  14 ,  Phillip T Newton  11 ,  Nicolas J Pillon  15 ,  Gunnar Schulte  10 ,  Roger J Summers  9 ,  Ilga Mutule  12 ,  Edgars Suna  12 ,  Jesper V Olsen  8 ,  Peter Molenaar  16 ,  Jens Carlsson  3 ,  Volker M Lauschke  17 ,  Shane C Wright  18 ,  Tore Bengtsson  19
Affiliations
  • 1. Atrogi AB, Stockholm, Sweden; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Department of Physiology & Pharmacology, Section for Personalized Medicine and Drug Development, Karolinska Institutet, Stockholm, Sweden.
  • 2. Atrogi AB, Stockholm, Sweden.
  • 3. Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
  • 4. Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
  • 5. Cardio-Vascular Molecular & Therapeutics Translational Research Group, Northside Clinical School of Medicine, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia; Queensland University of Technology (QUT), School of Biomedical Sciences, Institute of Health and Biomedical Innovation, QLD, Australia.
  • 6. Department of Physiology & Pharmacology, Section for Personalized Medicine and Drug Development, Karolinska Institutet, Stockholm, Sweden.
  • 7. Novo Nordisk Foundation Centre for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Surgical Sciences, Uppsala University, Uppsala 75185, Sweden.
  • 8. Novo Nordisk Foundation Centre for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
  • 9. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
  • 10. Department of Physiology & Pharmacology, Section for Receptor Biology and Signaling, Karolinska Institutet, Stockholm, Sweden.
  • 11. Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden; Astrid Lindgren Children's Hospital, Stockholm, Sweden.
  • 12. Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia.
  • 13. Excellerate Bioscience, The Triangle, NG2 Business Park, Nottingham, UK.
  • 14. Excellerate Bioscience, The Triangle, NG2 Business Park, Nottingham, UK; School of Life Sciences, The Medical School, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
  • 15. Department of Physiology & Pharmacology, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
  • 16. Cardio-Vascular Molecular & Therapeutics Translational Research Group, Northside Clinical School of Medicine, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
  • 17. Department of Physiology & Pharmacology, Section for Personalized Medicine and Drug Development, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden; Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, Tübingen, Germany. Electronic address: [email protected].
  • 18. Department of Physiology & Pharmacology, Section for Personalized Medicine and Drug Development, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden. Electronic address: [email protected].
  • 19. Atrogi AB, Stockholm, Sweden; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden. Electronic address: [email protected].
PMID: 40555230 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.

Keywords
BRET; GLP-1; GPCR; GRK; beta-2 agonists; biased agonism; diabetes; metabolism; obesity; skeletal muscle.
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