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Research ArticleEndocrine and Diabetes

MLR-1023 Is a Potent and Selective Allosteric Activator of Lyn Kinase In Vitro That Improves Glucose Tolerance In Vivo

Michael S. Saporito, Alexander R. Ochman, Christopher A. Lipinski, Jeffrey A. Handler and Andrew G. Reaume
Journal of Pharmacology and Experimental Therapeutics July 2012, 342 (1) 15-22; DOI: https://doi.org/10.1124/jpet.112.192096
Michael S. Saporito
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Alexander R. Ochman
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Christopher A. Lipinski
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Jeffrey A. Handler
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Andrew G. Reaume
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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 Vmax of Lyn with an EC50 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.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.192096.

  • ABBREVIATIONS:

    MLR-1023
    2(1H)-pyrimidinone,5-(3-methylphenoxy)
    DPP-IV
    dipeptidyl peptidase-4
    ELISA
    enzyme-linked immunosorbent assay
    GLP-1
    glucagon-like peptide-1
    IRS-1
    insulin receptor substrate-1
    OGTT
    oral glucose tolerance test
    PPAR
    peroxisome proliferator-activated receptor
    T2D
    type 2 diabetes
    L-165,041
    [4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]acetic acid
    P32/98
    N-[((2S,3S)-2-amino-3-methylpentanoyl]-1,3-thiazolidine
    A-769,662
    6,7-dihydro-4-hydroxy-3-(2′-hydroxy[1,1′-biphenyl]-4-yl)-6-oxo-thieno[2,3-b]pyridine-5-carbonitrile
    L-783,281
    2-[2-(1,1-dimethyl-2-propenyl)-1H-indol-3-yl]-3,6-dihydroxy-5-[7-(3-methyl-2-butenyl)-1H-indol-3-yl]-2,5-cyclohexadiene-1,4-dione.

  • Received January 18, 2012.
  • Accepted April 2, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 1
1 Jul 2012
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Research ArticleEndocrine and Diabetes

The Lyn Kinase Activator MLR-1023 Induces Glycemic Control

Michael S. Saporito, Alexander R. Ochman, Christopher A. Lipinski, Jeffrey A. Handler and Andrew G. Reaume
Journal of Pharmacology and Experimental Therapeutics July 1, 2012, 342 (1) 15-22; DOI: https://doi.org/10.1124/jpet.112.192096

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Research ArticleEndocrine and Diabetes

The Lyn Kinase Activator MLR-1023 Induces Glycemic Control

Michael S. Saporito, Alexander R. Ochman, Christopher A. Lipinski, Jeffrey A. Handler and Andrew G. Reaume
Journal of Pharmacology and Experimental Therapeutics July 1, 2012, 342 (1) 15-22; DOI: https://doi.org/10.1124/jpet.112.192096
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