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 ␣, ␦, and ␥ receptors or glucagon-like peptide-1 receptors or inhibit dipeptidyl peptidase-4 or ␣-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.

The Lyn Kinase Activator MLR-1023 Is a Novel Insulin Receptor Potentiator that Elicits a Rapid-Onset and Durable Improvement in Glucose Homeostasis in Animal Models of Type 2 Diabetes

“…With chronic administration, MLR-1023 administration produced a sustainable decrease in blood glucose levels and decreased HbA1c levels and prevented the loss of pancreatic ␤-cells. These results, coupled with data from the companion article (Saporito et al, 2012b), show that MLR-1023 represents a novel class of insulin sensitizer distinct from the TZDs. These results indicate that MLR-1023 is a potential therapeutic for the treatment of T2D.…”

“…Unlike TZDs, MLR-1023 did not activate PPARs (Saporito et al, 2012b), produced a rapid onset of action, and did not cause weight gain. With chronic administration, MLR-1023 administration produced a sustainable decrease in blood glucose levels and decreased HbA1c levels and prevented the loss of pancreatic ␤-cells.…”

“…In addition, insulin receptor activation leads to phosphorylation of Lyn kinase, suggesting a potential feedback regulatory loop between insulin receptor activation and Lyn kinase (Anderwald et al, 2002). In vivo, MLR-1023 administration reduced blood glucose levels in mice subjected to an oral glucose tolerance test (OGTT) without increasing insulin secretion (Saporito et al, 2012b). The known involvement of Lyn kinase in modulating insulin signaling and the effects of MLR-1023 on blood glucose levels suggested that MLR-1023 regulated glucose levels through the modification of insulin-signaling.…”

“…This compound was identified as a candidate for T2D using an in vivo phenotypic screen (Saporito et al, 2012a). In the companion article, we show that MLR-1023 is a direct, selective, and potent activator of the nonreceptor Src-related Lyn kinase (Saporito et al, 2012b). In adipocytes, activated Lyn kinase phosphorylates insulin receptor substrate-1 (IRS-1) and increases insulin receptor signaling (Mü ller et al, 2000(Mü ller et al, , 2005.…”

ATP-Binding Cassette Transporters, Atherosclerosis, and Inflammation

“…162,163 In addition, there is some evidence that increased platelet production may precede the onset of acute coronary syndromes. 164 These studies suggest that rHDL infusions or Lyn kinase activators such as tolimidone 165 may play a role in the suppression of platelet overproduction in these settings.…”