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Mechanism and cellular actions of the potent AMPK inhibitor BAY-3827

Fraguas Bringas, Conchita ; Ahangar, Mohd Syed ; Cuenco, Joyceline ; Liu, Hongling ; Addinsall, Alex B. ; Lindahl, Maria LU ; Ovens, Ashley J. ; Febbraio, Mark A. ; Foretz, Marc and Göransson, Olga LU orcid , et al. (2025) In Science Advances 11(34).
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Advances
volume
11
issue
34
article number
eadx2434
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:105015269817
  • pmid:40845097
ISSN
2375-2548
DOI
10.1126/sciadv.adx2434
language
English
LU publication?
yes
id
05e61c90-6e23-4536-80cf-125f22d4b246
date added to LUP
2025-10-20 17:23:32
date last changed
2025-10-21 03:00:04
@article{05e61c90-6e23-4536-80cf-125f22d4b246,
  abstract     = {{<p>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.</p>}},
  author       = {{Fraguas Bringas, Conchita and Ahangar, Mohd Syed and Cuenco, Joyceline and Liu, Hongling and Addinsall, Alex B. and Lindahl, Maria and Ovens, Ashley J. and Febbraio, Mark A. and Foretz, Marc and Göransson, Olga and Scott, John W. and Zeqiraj, Elton and Sakamoto, Kei}},
  issn         = {{2375-2548}},
  language     = {{eng}},
  number       = {{34}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Advances}},
  title        = {{Mechanism and cellular actions of the potent AMPK inhibitor BAY-3827}},
  url          = {{http://dx.doi.org/10.1126/sciadv.adx2434}},
  doi          = {{10.1126/sciadv.adx2434}},
  volume       = {{11}},
  year         = {{2025}},
}