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

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.
• 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.
• 20. Atrogi AB, Stockholm, Sweden; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

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.

G蛋白偶联受体（GPCR）的偏向性激动作用为开发更安全的药物提供了可能。当前的研究主要集中在平衡G蛋白与β-抑制蛋白（β-arrestin）信号通路；然而，其他信号转导分子，如GPCR激酶（GRKs），却仍未得到充分研究。GRK2对于β2肾上腺素受体（β2AR）介导的葡萄糖摄取至关重要，但经典的β2AR激动剂因其通过Gs蛋白/环磷酸腺苷（cAMP）通路引发的心脏副作用以及β-抑制蛋白依赖的受体脱敏作用，在血糖管理领域被视为较差的临床候选药物。通过基于配体的虚拟筛选和化合物结构优化，我们开发出了一系列偏好激活GRK磷酸化通路的β2AR通路选择性激动剂。这些化合物在高血糖和肥胖的临床前模型中表现优异，与标准β2受体激动剂相比，其心脏副作用风险更低；与肠促胰岛素类似物（incretin mimetics）相比，其肌肉相关副作用风险也更低。此外，先导化合物在药代动力学方面表现理想，并在安慰剂对照临床试验中显示出良好的耐受性。因此，偏向GRK通路的β2AR部分激动剂有望成为治疗2型糖尿病和肥胖症的口服药物替代方案，以替代目前需要注射给药的肠促胰岛素类似物。

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

关键词: 生物发光共振能量转移, 胰高血糖素样肽-1, G蛋白偶联受体, G 蛋白偶联受体激酶, β2激动剂, 偏向性激动作用, 糖尿病, 代谢, 肥胖症, 骨骼肌，流式抗体，佰乐博，佰乐博生物