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

Aikaterini Motso¹, Benjamin Pelcman², Anastasia Kalinovich², Nour Aldin Kahlous³, Muhammad Hamza Bokhari⁴, Nodi Dehvari², Carina Halleskog², Erik Waara², Jasper de Jong², Elizabeth Cheesman⁵, Christine Kallenberg², Gopala Krishna Yakala², Praerona Murad², Erika Wetterdal², Pia Andersson², Sten van Beek², Anna Sandström², Diane Natacha Alleluia², Emanuela Talamonti², Sonia Youhanna⁶, Pierre Sabatier⁷, Claire Koenig⁸, Sabine Willems⁶, Aurino M Kemas⁶, Dana S Hutchinson⁹, Seungmin Ham⁹, Lukas Grätz¹⁰, Jan Voss¹⁰, Jose G Marchan-Alvarez¹¹, Martins Priede¹², Krista Jaunsleine¹², Jana Spura¹², Vadims Kovada¹², Linda Supe¹², Leigh A Stoddart¹³, Nicholas D Holliday¹⁴, Phillip T Newton¹¹, Nicolas J Pillon¹⁵, Gunnar Schulte¹⁰, Roger J Summers⁹, Ilga Mutule¹², Edgars Suna¹², Jesper V Olsen⁸, Peter Molenaar¹⁶, Jens Carlsson³, Volker M Lauschke¹⁷, Shane C Wright¹⁸, Tore Bengtsson¹⁹

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

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

Aikaterini Motso et al. Cell. 2025.

. 2025 Sep 18;188(19):5142-5156.e23.

doi: 10.1016/j.cell.2025.05.042. Epub 2025 Jun 23.

Authors

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

Erratum in

GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity.
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. Motso A, et al. Cell. 2025 Sep 18;188(19):5429-5431. doi: 10.1016/j.cell.2025.08.022. Epub 2025 Aug 29. Cell. 2025. PMID: 40882626 No abstract available.

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 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 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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Conflict of interest statement

Declaration of interests T.B. is co-founder of Atrogi AB and Sigrid Therapeutics. B.P. and N.D. own stocks in Atrogi AB. A.K., M.H.B., N.D., C.H., E.W., J.d.J., C.K., G.K.Y., P. Murad, E.W., P.A., S.v.B., A.S., D.N.A., and E.T. are currently employed by or have been employed by Atrogi AB. B.P. and T.B. are inventors of patent applications claiming compounds used in this work. B.P. is a consultant for Atrogi AB. Atrogi AB funded the clinical trial. V.M.L. is co-founder, CEO, and a shareholder of HepaPredict AB as well as co-founder and shareholder of Shanghai Hepo Biotechnology Ltd. L.A.S. and N.D.H. are employed by Excellerate.

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

Affiliations

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

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Medical

Research Materials