Oral drugs approved for the treatment of type 2 diabetes are heterogeneous in their mechanisms, safety profiles, and tolerability, and their utility is limited by side-effect profile and/or limited efficacy. MLR-1023 [tolimidone; 5-(3-methylphenoxy)-2(1H)-pyrimidinone] was discovered in a phenotypic screening platform designed to uncover new therapeutically beneficial activities of small molecules. MLR-1023 administration significantly lowered blood glucose in a mouse oral glucose tolerance test. In these studies, Saporito et al. demonstrated that MLR-1023 reduced blood glucose levels without increasing insulin secretion in vivo. MLR-1023 did not activate peroxisome proliferator-activated α, δ, and γ receptors or GLP-1 receptors and did not inhibit DPP-IV or α-glucosidase enzyme activity. MLR-1023 activated the non–receptor-linked kinase Lyn by increasing the Vmax of Lyn in an ATP binding-site-independent manner. Glucose-lowering effects of MLR-1023 were absent in Lyn knockout mice, confirming the link between Lyn kinase and blood glucose lowering. These studies show that MLR-1023 selectively activated Lyn kinase through an allosteric mechanism in vitro and that Lyn kinase activity is critical for MLR-1023-mediated blood glucose-lowering activity in vivo. These results, coupled with the results of the companion article (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.
See article at J Pharmacol Exp Ther 2012, 342:15–22.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics