MLR-1023 is a potent and selective allosteric activator of Lyn kinase in vitro that improves glucose tolerance in vivo.

Abstract

2(1H)-pyrimidinone,5-(3-methylphenoxy) (MLR-1023) is a candidate for the treatment of type 2 diabetes. The current studies were aimed at determining the mechanism by which MLR-1023 mediates glycemic control. In these studies, we showed that MLR-1023 reduced blood glucose levels without increasing insulin secretion in vivo. We have further determined that MLR-1023 did not activate peroxisome proliferator-activated α, δ, and γ receptors or glucagon-like peptide-1 receptors or inhibit dipeptidyl peptidase-4 or α-glucosidase enzyme activity. However, in an in vitro broad kinase screen MLR-1023 activated the nonreceptor-linked Src-related tyrosine kinase Lyn. MLR-1023 increased the V(max) of Lyn with an EC(50) of 63 nM. This Lyn kinase activation was ATP binding site independent, indicating that MLR-1023 regulated the kinase through an allosteric mechanism. We have established a link between Lyn activation and blood glucose lowering with studies showing that the glucose-lowering effects of MLR-1023 were abolished in Lyn knockout mice, consistent with existing literature linking Lyn kinase and the insulin-signaling pathway. In summary, these studies describe MLR-1023 as a unique blood glucose-lowering agent and show that MLR-1023-mediated blood glucose lowering depends on Lyn kinase activity. These results, coupled with other results (J Pharmacol Exp Ther 342:23-32, 2012), suggest that MLR-1023 and Lyn kinase activation may be a new treatment modality for type 2 diabetes.

• Authors: Michael S Saporito, Alexander R Ochman, Christopher A Lipinski, Jeffrey A Handler, Andrew G Reaume
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 342 Issue 1 Pg. 15-22 (Jul 2012) ISSN: 1521-0103 [Electronic] United States
• PMID: 22473614 (Publication Type: Journal Article)

Chemical References

• Blood Glucose
• Glp1r protein, mouse
• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents
• Insulin
• Peroxisome Proliferator-Activated Receptors
• Protein Kinase Inhibitors
• Pyrimidinones
• Receptors, Glucagon
• Adenosine Triphosphate
• lyn protein-tyrosine kinase
• src-Family Kinases
• alpha-Glucosidases
• Dipeptidyl Peptidase 4
• 5-(3-methylphenoxy)-2(1H)-pyrimidinone

Topics

• Adenosine Triphosphate (metabolism)
• Allosteric Regulation (drug effects)
• Animals
• Blood Glucose (drug effects, metabolism)
• Diabetes Mellitus, Type 2 (blood, drug therapy, metabolism)
• Dipeptidyl Peptidase 4 (metabolism)
• Glucagon-Like Peptide-1 Receptor
• Glucose Tolerance Test (methods)
• Hypoglycemic Agents (pharmacology)
• Insulin (metabolism)
• Insulin Secretion
• Male
• Mice
• Mice, Inbred ICR
• Mice, Knockout
• Peroxisome Proliferator-Activated Receptors (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidinones (pharmacology)
• Receptors, Glucagon (metabolism)
• Signal Transduction (drug effects)
• alpha-Glucosidases (metabolism)
• src-Family Kinases (antagonists & inhibitors, metabolism)