Description
A-
769662 is a small molecule thienopyridone that activates AMPK directly in cell-
free assays (EC
50 = 116 nM) and intact cells by allosterically activating AMPK and inhibiting its dephosphorylation on Thr
172. A-
769662 specifically activates β1 subunit-
containing AMPK heterotrimers, and its effects are independent of kinases upstream of AMPK. A-
769662 has been used to stimulate CYP450-
mediated fatty acid oxidation, inhibit adipocyte differentiation, explore glucose uptake in skeletal muscle, and promote endothelial cell survival during metabolic stress.
Uses
A 769662 is an AMP-activated protein kinase (AMPK) activiator. A 769662 selectively activates cardiac AMPK heterotrimeric complexes contg. α2/β1-subunits.
Definition
ChEBI: 4-hydroxy-3-[4-(2-hydroxyphenyl)phenyl]-6-oxo-7H-thieno[2,3-b]pyridine-5-carbonitrile is a member of biphenyls.
Biological Activity
Potent, reversible AMP-activated protein kinase (AMPK) activator (EC 50 = 0.8 μ M) that displays selectivity towards β 1 subunit-containing heterotrimers. Inhibits fatty acid synthesis (IC 50 = 3.2 μ M) and decreases plasma glucose and triglyceride levels in vivo .
Background
A-769662 is a potent activator of AMP-activated protein kinase by allosterically binding to the β and γ subunits and by inhibiting dephosphorylation of AMPK on Thr172. This small molecule selectively targets AMPK heterotrimers containing the β1 subunit. A-769662 has been shown to stimulate purified rat liver AMPK and inhibit fatty acid synthesis in rat hepatocytes. Treatment of adipocytes with A-769662 inhibits cell differentiation, leads to over-activation of AMPK, and inactivation of acetyl-CoA carboxylase, making this an interesting compound when studying obesity.
References
[1] JOHN W SCOTT. Thienopyridone drugs are selective activators of AMP-activated protein kinase beta1-containing complexes.[J]. Chemistry & biology, 2008, 15 11: 1220-1230. DOI:
10.1016/j.chembiol.2008.10.005[2] BARBARA COOL. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome.[J]. Cell metabolism, 2006, 3 6: 403-416. DOI:
10.1016/j.cmet.2006.05.005[3] YI ZHOU. Inhibitory effects of A-769662, a novel activator of AMP-activated protein kinase, on 3T3-L1 adipogenesis.[J]. Biological & pharmaceutical bulletin, 2009, 32 6: 993-998. DOI:
10.1248/bpb.32.993[4] ALEJANDRO VAZQUEZ-MARTIN. Activation of AMP-activated protein kinase (AMPK) provides a metabolic barrier to reprogramming somatic cells into stem cells.[J]. Cell Cycle, 2012, 11 5: 974-989. DOI:
10.4161/cc.11.5.19450[5] SERGE DUCOMMUN. Enhanced activation of cellular AMPK by dual-small molecule treatment: AICAR and A769662.[J]. American journal of physiology. Endocrinology and metabolism, 2014, 306 6: E688-96. DOI:
10.1152/ajpendo.00672.2013
