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Research ArticleArticle

Disruption of Insulin-Like Growth Factor-1 Signaling and Down-Regulation of Cdc2 by SC-ααδ9, a Novel Small Molecule Antisignaling Agent Identified in a Targeted Array Library

Andreas Vogt, Robert L. Rice, Catherine E. Settineri, Fumiaki Yokokawa, Shiho Yokokawa, Peter Wipf and John S. Lazo
Journal of Pharmacology and Experimental Therapeutics November 1998, 287 (2) 806-813;
Andreas Vogt
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Robert L. Rice
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Catherine E. Settineri
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Fumiaki Yokokawa
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Shiho Yokokawa
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Peter Wipf
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John S. Lazo
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Abstract

We previously reported the generation of a library of hydrophobic oxazole-based small molecules designed as inhibitors of phosphatases involved in cellular signaling and cell cycle control. One member of the targeted array library, 4-(benzyl-(2-[(2,5-diphenyl-oxazole-4-carbonyl)-amino]-ethyl)-carbamoyl)-2-decanoylamino butyric acid (SC-ααδ9), inhibited cell growth in the G0/G1 phase of the cell cycle. To investigate potential mechanisms for SC-ααδ9 antiproliferative activity, we have used mouse embryonic fibroblasts transformed with simian virus 40 large T antigen mouse embryonic fibroblasts as a model system for a malignant phenotype that depends on overexpression of cell cycle regulators and autocrine stimulation by insulin-like growth factor-1. Structure-activity relationship studies with SC-ααδ9 and four library congeners demonstrated that antiproliferative activity was not a result of overall hydrophobicity. Rather, SC-ααδ9 decreased insulin-like growth factor-1 receptor tyrosine phosphorylation, receptor expression, mitogen-activated protein kinase activation and levels of the cyclin-dependent kinase Cdc2. Less toxic congeners only partially affected receptor expression, receptor tyrosine phosphorylation and Cdc2 levels. Thus SC-ααδ9, which is structurally distinct from other known small molecules that decrease intracellular Cdc2 levels, has profound effects on intracellular signaling. Furthermore, SC-ααδ9, but not vanadate or okadaic acid, selectively inhibited the growth of simian virus 40 large T antigen mouse embryonic fibroblasts compared to the parental cells. These results suggest that overexpression of Cdc2 and increased dependence on insulin-like growth factor-1 autocrine stimulation are responsible for the increased sensitivity of simian virus 40 large T antigen mouse embryonic fibroblasts to SC-ααδ9. The SC-ααδ9 pharmacophore could be a useful platform for the development of novel antisignaling agents.

Footnotes

  • Send reprint requests to: Prof. John S. Lazo, University of Pittsburgh, School of Medicine, Department of Pharmacology, Pittsburgh, PA 15261.

  • 1 This work was supported by Army Breast Cancer Grant DAMD 17-1-7229, Army Breast Cancer Predoctoral Fellowship DAMD 17-94-J4103, The Fiske Drug Discovery Fund and United States Public Health Service National Institutes of Health Grants CA-61229, CA-78039 and GM-55433.

  • Abbreviations:
    SC-ααδ9
    4-(benzyl-(2-[(2,5-diphenyl-oxazole-4-carbonyl)-amino]-ethyl)-carbamoyl)-2-decanoylamino butyric acid
    DSPase
    dual specificity phosphatase
    IGF-1
    Insulin-like growth factor-1
    MEF
    mouse embryonic fibroblasts
    MAPK
    mitogen-activated protein kinase
    MTT
    3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide
    PSTPase
    protein serine/threonine phosphatase
    PTPase
    protein tyrosine phosphatase
    SDS-PAGE
    sodium dodecyl sulfate-polyacrylamide gel electrophoresis
    SV40
    simian virus 40 large T antigen
    FBS
    fetal bovine serum
    DMSO
    dimethylsulfoxide
    HEPES
    N-hydroxyethyl piperazine-N′-2-ethylsulfonic acid
    PMSF
    phenylmethylsulfonyl fluoride
    DTT
    dithiothreitol
    • Received March 23, 1998.
    • Accepted June 21, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 2
1 Nov 1998
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Research ArticleArticle

Disruption of Insulin-Like Growth Factor-1 Signaling and Down-Regulation of Cdc2 by SC-ααδ9, a Novel Small Molecule Antisignaling Agent Identified in a Targeted Array Library

Andreas Vogt, Robert L. Rice, Catherine E. Settineri, Fumiaki Yokokawa, Shiho Yokokawa, Peter Wipf and John S. Lazo
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 806-813;

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Research ArticleArticle

Disruption of Insulin-Like Growth Factor-1 Signaling and Down-Regulation of Cdc2 by SC-ααδ9, a Novel Small Molecule Antisignaling Agent Identified in a Targeted Array Library

Andreas Vogt, Robert L. Rice, Catherine E. Settineri, Fumiaki Yokokawa, Shiho Yokokawa, Peter Wipf and John S. Lazo
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 806-813;
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