{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Bringas CF"],"funding":["Wellcome Trust"],"pagination":["eadx2434"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12372887"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["11(34)"],"pubmed_abstract":["Inhibition of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is under increasing investigation for its therapeutic potential in many diseases. Existing AMPK inhibitors are however limited, with poor selectivity and substantial off-target effects. Here, we provide mechanistic insights and describe the cellular selectivity of the recently identified AMPK inhibitor BAY-3827. A 2.5-Å cocrystal structure of the AMPK kinase domain with BAY-3827 revealed distinct features including a disulfide bridge between the αD helix Cys106 and the activation loop residue Cys174. This bridge appears to stabilize the activation loop such that Asn162 repositions the Asp-Phe-Gly (DFG) motif Phe158 toward the C-terminal lobe, displacing His137 and disrupting the regulatory spine, promoting an inactive kinase state. In hepatocytes, BAY-3827 blocked AMPK activator (MK-8722)-mediated phosphorylation of ACC1 and corresponding inhibition of lipogenesis. Transcriptome analysis revealed that BAY-3827 down-regulated ~30% of MK-8722-stimulated AMPK-dependent genes. We establish the molecular and cellular basis of BAY-3827's selectivity and utility for delineating AMPK functions while highlighting its limitations."],"journal":["Science advances"],"pubmed_title":["Mechanism and cellular actions of the potent AMPK inhibitor BAY-3827."],"pmcid":["PMC12372887"],"funding_grant_id":["222531/Z/21/Z"],"pubmed_authors":["Liu H","Goransson O","Ahangar MS","Scott JW","Sakamoto K","Addinsall AB","Cuenco J","Febbraio MA","Lindahl M","Foretz M","Zeqiraj E","Ovens AJ","Bringas CF"],"additional_accession":[]},"is_claimable":false,"name":"Mechanism and cellular actions of the potent AMPK inhibitor BAY-3827.","description":"Inhibition of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is under increasing investigation for its therapeutic potential in many diseases. Existing AMPK inhibitors are however limited, with poor selectivity and substantial off-target effects. Here, we provide mechanistic insights and describe the cellular selectivity of the recently identified AMPK inhibitor BAY-3827. A 2.5-Å cocrystal structure of the AMPK kinase domain with BAY-3827 revealed distinct features including a disulfide bridge between the αD helix Cys106 and the activation loop residue Cys174. This bridge appears to stabilize the activation loop such that Asn162 repositions the Asp-Phe-Gly (DFG) motif Phe158 toward the C-terminal lobe, displacing His137 and disrupting the regulatory spine, promoting an inactive kinase state. In hepatocytes, BAY-3827 blocked AMPK activator (MK-8722)-mediated phosphorylation of ACC1 and corresponding inhibition of lipogenesis. Transcriptome analysis revealed that BAY-3827 down-regulated ~30% of MK-8722-stimulated AMPK-dependent genes. We establish the molecular and cellular basis of BAY-3827's selectivity and utility for delineating AMPK functions while highlighting its limitations.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Aug","modification":"2026-05-09T10:41:26.925Z","creation":"2026-04-08T00:48:45.296Z"},"accession":"S-EPMC12372887","cross_references":{"pubmed":["40845097"],"doi":["10.1126/sciadv.adx2434"]}}