Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription

Abstract

SB-216763 and SB-415286 are novel, potent and selective cell permeable inhibitors of GSK-3. Therefore, these compounds represent valuable pharmacological tools with which the role of GSK-3 in cellular signalling can be further elucidated. Furthermore, development of similar compounds may be of use therapeutically in disease states associated with elevated GSK-3 activity such as non-insulin dependent diabetes mellitus and neurodegenerative disease.

Synthesis and Initial in Vivo Studies with [11C]SB-216763: The First Radiolabeled Brain Penetrative Inhibitor of GSK-3

“…29 SB-216763 inhibits the enzyme in an ATP competitive manner, has good selectivity for GSK-3 over other protein kinases, and has been widely used in preclinical studies with promising results to date. 30 While a synthesis of [ 11 C]SB-216763 was reported in 2011 by Zheng and co-workers, 27 no biological evaluation of the radiotracer has been reported to date.…”

FR258900, a Novel Glycogen Phosphorylase Inhibitor Isolated from Fungus No. 138354

“…In the present study, we demonstrated that glycogen phosphorylase inhibitor could activate glycogen synthesis, suggesting that phosphorylase inhibitors should also be effective in promoting hepatic glycogen synthesis in the absorptive state. We describe in our accompanying paper1 [7] whether FR258900 can improve oral glucose disposal by increasing liver glycogen synthesis, and also lower blood glucose by reducing hepatic glucose output in diabetic animal models. Glycogen phosphorylase 2.5 Glucose-6-phosphatase Ͼ200…”

“…Glycogen synthase activity was measured as reported previously [7]. Primary rat hepatocytes were cultured in collagen-coated 90 mm diameter dishes, and treated with FR258900, glucagon or insulin for 2 hours.…”

“…Active glycogen synthase and total glycogen synthase were determined in the absence or presence of the allosteric activator G-6-P, respectively. Glycogen synthase activity is expressed as the activity ratio (ϪG-6-P/ϩG-6-P) [7]. Glycogen synthase is post-translationally modified by phosphorylation that directly inhibits the enzyme.…”

“…Inorganic phosphate was measured by addition of 1M HCl containing 10 mg/ml ammonium molybdate and 0.38 mg/ml malachite green, and the absorbance was determined at 620 nm [9]. Glycogen synthase kinase-3 (GSK-3) activity was measured according to the method described by Coghlan et al [7] using recombinant GSK-3b (Sigma) and phospho GS-2 peptide (Upstate Biotechnology, Lake Placid, NY) as a substrate. Glucose-6-phosphatase (G-6-Pase) activity was assayed according to the method described previously [10].…”