A-769662

BackgroundAMP-activated protein kinases (AMPK) are a family of protein kinases that are directly activated in response to increased cellular levels of AMP and are thus able to act as a sensor for lowered cellular energy levels. In response to low cellular energy levels, the activation of AMPK causes an increase in cellular levels of ATP by increasing metabolism of glucose and fatty acids.

Activation of AMPK is of clinical importance, as metformin, a biguanide drug (used to treat type II diabetes), exerts its main therapeutic effect by activating AMPK in the liver. However, this is through an indirect mechanism and does not occur in other tissues (probably because metformin is not readily taken up in other cell types). In experimental studies, the cell-permeable drug AICAR-riboside has been used to activate AMPK. AICAR-riboside is readily taken up and metabolised to ZMP, which in turn can activate AMPK. However, ZMP also activates a range of other AMP-activated enzymes, including glycogen phosphorylase and fructose 1:6 bisphosphatase. A-769662 is a cell permeable drug, that potently activates AMPK in cells (EC₅₀ 120 nM) and, unlike AICAR-riboside , does not activate other AMP target enzymes [1, 2]. When tested against a panel of 76 protein kinases, A-769662 was observed to only significantly inhibit the activity of PIM1 and PIM3 (>50% inhibition).

References

1 Cool, B., Zinker, B., Chiou, W., Kifle, L., Cao, N., Perham, M., Dickinson, R., Adler, A., Gagne, G., Iyengar, R., Zhao, G., Marsh, K., Kym, P., Jung, P., Camp, H. S. and Frevert, E. (2006) Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome.Cell Metab 3, 403-16

2 Sanders, M. J., Ali, Z. S., Hegarty, B. D., Heath, R., Snowden, M. A. and Carling, D. (2007) Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family.J Biol Chem 282, 32539-48