title: 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.affiliation: Melior Discovery, Inc., 860 Springdale Drive, Exton, PA 19341, USA. msaporito@meliordiscovery.com
authors.forename: Michael S
authors.initials: MS
authors.lastname: Saporito
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Ochman
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lipinski
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Handler
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Reaume
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test / Q000379:methods; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000520:alpha-Glucosidases / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D047492:Peroxisome Proliferator-Activated Receptors; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D018027:Receptors, Glucagon; D000255:Adenosine Triphosphate; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D000520:alpha-Glucosidases; D018819:Dipeptidyl Peptidase 4; C576397:5-(3-methylphenoxy)-2(1H)-pyrimidinone