Background:

A-769662 is a potent activator of AMPK with EC50 value of 0.8 μM in vitro[1].

AMPK(AMP-activated protein kinase) is a serine/threonine protein kinase which is formed by three proteins: α,β and γ subunits. They play important roles in both the activity and stabilities of AMPK. AMPK functions as sensors of cellular energy by detecting and reacting to the change of AMP: ATP ratio. AMPK plays an important role in regulating intracellular energy metabolism. AMPK inhibits ATP-consuming pathways containing cholesterol synthesis, fatty acid synthesisand gluconeogenesis. AMPK stimulates fatty acid oxidation and glycolysis which are ATP-generating processes. AMPK inhibits gluconeogenesis by suppressing the expression of glucose-6-phosphatase and PEPCK wich are two key gluconeogenic enzymes.[1]

A-769662 belongs to the thienopyridone family. It activates the activity of purified AMPK from diffrent tissues with a dose-dependent manner. A-769662 activated the activity of AMPK extracted from human embryonic kidney cells (HEKs), rat muscle, or rat heart with EC50 values of 1.1 mM, 1.9 mM, or 2.2mM, respectively. A-769662 inhibited the synthesis of fatty acid with IC50 value of 3.2mM in primary rat hepatocytes.[1] A769662 also has inhibition effect on the 26S proteasome with an AMPK-independent mechanism. A769662 does not inhibit the proteolytic activities of the 20S core subunit which is a novel mechanism. A769662 can cause the arrest of cell cycle by inhibiting the 26S proteasome[2]. A-769662 activates AMPK in an allosterically manner. It also inhibits Thr-172 dephosphorylation of AMPK.[3]

In mice treated with dose of 30mg/kg, A-769662 decreased the expression of FAS, G6Pase, and PEPCK in liver of. It also lowered plasma glucose by 40% and reduced body weight gain.[1]

参考文献:
[1].  Cool B, Zinker B, Chiou W, Kifle L, Cao N, Perham M, Dickinson R, Adler A, Gagne G, Iyengar R et al: Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 2006, 3(6):403-416.
[2].  Moreno D, Knecht E, Viollet B, Sanz P: A769662, a novel activator of AMP-activated protein kinase, inhibits non-proteolytic components of the 26S proteasome by an AMPK-independent mechanism. FEBS Lett 2008, 582(17):2650-2654.
[3].  Sanders MJ, Ali ZS, Hegarty BD, Heath R, Snowden MA, Carling D: 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 2007, 282(45):32539-32548.