2. Academic Validation
  3. GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity

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

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: volker.lauschke@ki.se.
  • 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: shane.wright@ki.se.
  • 19 Atrogi AB, Stockholm, Sweden; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden. Electronic address: tore.bengtsson@su.se.
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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