AMP-Activated Protein Kinase (AMPK) Activator

A769662 (1) is a cell-permeable activator of AMP-activated protein kinase (AMPK).¹⁾ 1 was found to directly stimulate partially purified rat liver AMPK with EC₅₀ = 0.8 μM and inhibited fatty acid synthesis in primary rat hepatocytes with IC₅₀ = 3.2 μM.¹⁾
1 provided significant stimulation to purified rat liver AMPK (EC₅₀ = 116 nM) and stimulation of the kinase by 1 was 50 times more potent than that by AMP.²⁾ The mechanism of activation of AMPK by 1 is allosteric and involves inhibiting dephosphorylation of the kinase on Thr-172.³⁾ 1 inhibits reprogramming of somatic cells into induced pluripotent stem cells (iPSCs)⁴⁾ and proliferation of mesenchymal stem cells.⁵⁾

References

• 1) Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome
  • B. Cool, B. Zinker, W. Chiou, L. Kifle, N. Cao, M. Perham, R. Dickinson, A. Adler, G. Gagne, R. Iyengar, G. Zhao, K. Marsh, P. Kym, P. Jung, H. S. Camp, E. Frevert, Cell Metab. 2006, 3, 403.
• 2) Mechanism of Action of A-769662, a Valuable Tool for Activation of AMP-activated Protein Kinase
  • O. Göransson, A. McBride, S. A. Hawley, F. A. Ross, N. Shpiro, M. Foretz, B. Viollet, D. G. Hardie, K. Sakamoto, J. Biol. Chem. 2007, 282, 32549.
• 3) Defining the Mechanism of Activation of AMP-activated Protein Kinase by the Small Molecule A-769662, a Member of the Thienopyridone Family
  • M. J. Sanders, Z. S. Ali, B. D. Hegarty, R. Heath, M. A. Snowden, D. Carling, J. Biol. Chem. 2007, 282, 32539.
• 4) Mechanism of Action of A-769662, a Valuable Tool for Activation of AMP-activated Protein Kinase
  • A. Vazquez-Martin, L. Vellon, P. M Quirós, S. Cufí, E. R. de Galarreta, C. Oliveras-Ferraros, A. G. Martin, B. Martin-Castillo, C. López-Otín, J. A. Menendez, Cell Cycle 2012, 11, 974.
• 5) Role of AMP-activated protein kinase in regulating hypoxic survival and proliferation of mesenchymal stem cells
  • C. de Meester, A. D. Timmermans, M. Balteau, A. Ginion, V. Roelants, G. Noppe, P. E. Porporato, P. Sonveaux, B. Viollet, K. Sakamoto, O. Feron, S. Horman, J.-L. Vanoverschelde, C. Beauloye, L. Bertrand, Cardiovasc. Res. 2014, 101, 20.

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