Academic Journal
The pan-AMPK activator MK-8722 outperforms the AMPK activators SC4 and A-769662 in human endothelial cells.
| Τίτλος: | The pan-AMPK activator MK-8722 outperforms the AMPK activators SC4 and A-769662 in human endothelial cells. |
|---|---|
| Συγγραφείς: | Doshi H; Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07745 Jena, Germany., Spengler K; Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07745 Jena, Germany., Siniuk K; Leibniz Institute on Aging- Fritz Lipmann Institute (FLI), 07745 Jena, Germany., Groth M; Leibniz Institute on Aging- Fritz Lipmann Institute (FLI), 07745 Jena, Germany., Heyne E; Department of Cardiothoracic Surgery, Jena University Hospital, 07747 Jena, Germany., Schwarzer M; Department of Cardiothoracic Surgery, Jena University Hospital, 07747 Jena, Germany., Godbole A; Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07745 Jena, Germany., Gee YS; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia., Baell J; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia.; School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, People's Republic of China., Oakhill JS; Metabolic Signaling Laboratory, St. Vincent's Institute of Medical Research, Fitzroy 3065, Australia.; Faculty of Health Sciences, Australian Catholic University, Melbourne 3065, Australia., Henke A; Section of Experimental Virology, Institute of Medical Microbiology, Jena University Hospital, 07745 Jena, Germany., Heller R; Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07745 Jena, Germany. |
| Πηγή: | Bioscience reports [Biosci Rep] 2026 Oct 21; Vol. 46 (10). |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Portland Press on behalf of the Biochemical Society Country of Publication: England NLM ID: 8102797 Publication Model: Print Cited Medium: Internet ISSN: 1573-4935 (Electronic) Linking ISSN: 01448463 NLM ISO Abbreviation: Biosci Rep Subsets: MEDLINE |
| Imprint Name(s): | Publication: London : Portland Press on behalf of the Biochemical Society Original Publication: London : The Biochemical Society, c1981- |
| Ιατρικοί όροι (MeSH): | Thiophenes*/pharmacology , AMP-Activated Protein Kinases*/metabolism , Pyrones*/pharmacology , Endothelial Cells*/drug effects , Endothelial Cells*/enzymology , Enzyme Activators*/pharmacology , Resorcinols*/pharmacology, Enzyme Activation/drug effects ; Phosphorylation/drug effects ; Human Umbilical Vein Endothelial Cells/drug effects ; Humans ; Biphenyl Compounds |
| Περίληψη: | AMP-activated protein kinase (AMPK), a heterotrimeric serine/threonine protein kinase consisting of the catalytic α-subunit and regulatory β- and γ-subunits, regulates endothelial homeostasis. Consequently, it has emerged as a target for pharmacological activators in the treatment of endothelial dysfunction. However, the efficiency of these agonists may differ depending on the expression of different AMPK subunit isoforms in different cells and tissues, as these isoforms may form AMPK complexes with distinct activation profiles. The present study compares the effects of three direct AMPK activators in endothelial cells: MK-8722, a pan-AMPK activator; SC4, an intermediate activator with preference for AMPKα2; and A-769662, a β1-specific compound. We demonstrate that MK-8722 (0.1 to 10 μM) induces a robust and sustained, short- and long-term activation of AMPK, as evidenced by the phosphorylation of acetyl-CoA carboxylase and the inhibition of the mechanistic target of rapamycin complex 1 pathway. On an equimolar basis, MK-8722 was significantly more potent than SC4 and A-769662. This was associated with a significant antiviral effect of MK-8722 against herpes simplex virus type 1, whereas SC4 and A-769662 had no effect. At 10 μM, MK-8722 led to energy depletion and increased formation of mitochondrial and cytosolic reactive oxygen species due to inhibition of mitochondrial complex I. Under these conditions, liver kinase B1-mediated AMPK activation was observed but was not functionally relevant. We propose that the strong activation of AMPK by MK-8722 is related to the presence of different AMPK heterotrimers in endothelial cells. Therefore, targeting endothelial dysfunction pharmacologically may require pan-AMPK activators. (© 2026 The Author(s).) |
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| Grant Information: | N/A Deutsche Forschungsgemeinschaft (DFG); N/A Bundesministerium für Forschung, Technologie und Raumfahrt (BMBF); N/A Interdisciplinary Center for Clinical Research (IZKF), Jena; N/A Landesgraduiertenstipendium of the Free State of Thuringia |
| Contributed Indexing: | Keywords: A-769662; AMPK; AMPK activators; Endothelial cells; MK-8722; SC4 |
| Substance Nomenclature: | 0 (Thiophenes) P68477CD2C (4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile) EC 2.7.11.31 (AMP-Activated Protein Kinases) 0 (Pyrones) 0 (Biphenyl Compounds) 0 (Enzyme Activators) 0 (Resorcinols) |
| Entry Date(s): | Date Created: 20260908 Date Completed: 20260922 Latest Revision: 20260925 |
| Update Code: | 20260925 |
| PubMed Central ID: | PMC13598317 |
| DOI: | 10.1042/BSR20250408 |
| PMID: | 42708818 |
| Βάση Δεδομένων: | MEDLINE |
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