2. Academic Validation
  3. Mechanism of action of compound-13: an α1-selective small molecule activator of AMPK

Mechanism of action of compound-13: an α1-selective small molecule activator of AMPK

  • Chem Biol. 2014 Jul 17;21(7):866-79. doi: 10.1016/j.chembiol.2014.05.014.
Roger W Hunter 1,  Marc Foretz 2,  Laurent Bultot 3,  Morgan D Fullerton 4,  Maria Deak 3,  Fiona A Ross 5,  Simon A Hawley 5,  Natalia Shpiro 6,  Benoit Viollet 2,  Denis Barron 3,  Bruce E Kemp 7,  Gregory R Steinberg 4,  D Grahame Hardie 5,  Kei Sakamoto 8
Affiliations

Affiliations

  • 1 MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH Scotland, UK; Nestlé Institute of Health Sciences SA, EPFL Innovation Park, bâtiment G, 1015 Lausanne, Switzerland.
  • 2 Inserm, U1016, Institut Cochin, 24 rue du Faubourg Saint-Jacques, 75014 Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris cité, 75006 Paris, France.
  • 3 Nestlé Institute of Health Sciences SA, EPFL Innovation Park, bâtiment G, 1015 Lausanne, Switzerland.
  • 4 Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main West Street, Hamilton ON L8N 3Z5, Canada.
  • 5 Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
  • 6 MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH Scotland, UK.
  • 7 Protein Chemistry and Metabolism, St. Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy VIC 3065, Australia.
  • 8 MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH Scotland, UK; Nestlé Institute of Health Sciences SA, EPFL Innovation Park, bâtiment G, 1015 Lausanne, Switzerland. Electronic address: [email protected].
PMID: 25036776 DOI: 10.1016/j.chembiol.2014.05.014
Abstract

AMPK is a sensor of cellular energy status and a promising target for drugs aimed at metabolic disorders. We have studied the selectivity and mechanism of a recently described activator, C2, and its cell-permeable prodrug, C13. C2 was a potent allosteric activator of α1-complexes that, like AMP, also protected against Thr172 dephosphorylation. Compared with AMP, C2 caused only partial allosteric activation of α2-complexes and failed to protect them against dephosphorylation. We show that both effects could be fully restored by exchanging part of the linker between the autoinhibitory and C-terminal domains in α2, containing the equivalent region from α1 thought to interact with AMP bound in site 3 of the γ subunit. Consistent with our results in cell-free assays, C13 potently inhibited lipid synthesis in hepatocytes from wild-type and was largely ineffective in AMPK-knockout hepatocytes; its effects were more severely affected by knockout of α1 than of α2, β1, or β2.

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