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

Version 1

      Publication Details (including relevant citation   information): Saporito, Michael S., Ochman, Alexander   R., Lipinski, Christopher A., Handler, Jeffrey A., Reaume, Andrew   G., The Journal of pharmacology and experimental   therapeutics, 2012, 342 (1), pp   15-22

      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.

      Address (URL): http://dx.doi.org/10.1124/jpet.112.192096