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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Article

Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo

Yan Luo, Alexander R. Shoemaker, Xuesong Liu, Keith W. Woods, Sheela A. Thomas, Ron de Jong, Edward K. Han, Tongmei Li, Vincent S. Stoll, Jessica A. Powlas, Anatol Oleksijew, Michael J. Mitten, Yan Shi, Ran Guan, Thomas P. McGonigal, Vered Klinghofer, Eric F. Johnson, Joel D. Leverson, Jennifer J. Bouska, Mulugeta Mamo, Richard A. Smith, Emily E. Gramling-Evans, Bradley A. Zinker, Amanda K. Mika, Phong T. Nguyen, Tilman Oltersdorf, Saul H. Rosenberg, Qun Li and Vincent L. Giranda
Yan Luo
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Alexander R. Shoemaker
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Xuesong Liu
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Keith W. Woods
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Sheela A. Thomas
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Ron de Jong
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Edward K. Han
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Tongmei Li
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Vincent S. Stoll
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Jessica A. Powlas
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Anatol Oleksijew
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Michael J. Mitten
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Yan Shi
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Ran Guan
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Thomas P. McGonigal
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Vered Klinghofer
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Eric F. Johnson
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Joel D. Leverson
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Jennifer J. Bouska
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Mulugeta Mamo
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Richard A. Smith
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Emily E. Gramling-Evans
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Bradley A. Zinker
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Amanda K. Mika
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Phong T. Nguyen
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Tilman Oltersdorf
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Saul H. Rosenberg
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Qun Li
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Vincent L. Giranda
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DOI: 10.1158/1535-7163.MCT-05-0005 Published June 2005
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Abstract

The Akt kinases are central nodes in signal transduction pathways that are important for cellular transformation and tumor progression. We report the development of a series of potent and selective indazole-pyridine based Akt inhibitors. These compounds, exemplified by A-443654 (Ki = 160 pmol/L versus Akt1), inhibit Akt-dependent signal transduction in cells and in vivo in a dose-responsive manner. In vivo, the Akt inhibitors slow the progression of tumors when used as monotherapy or in combination with paclitaxel or rapamycin. Tumor growth inhibition was observed during the dosing interval, and the tumors regrew when compound administration was ceased. The therapeutic window for these compounds is narrow. Efficacy is achieved at doses ∼2-fold lower than the maximally tolerated doses. Consistent with data from knockout animals, the Akt inhibitors induce an increase in insulin secretion. They also induce a reactive increase in Akt phosphorylation. Other toxicities observed, including malaise and weight loss, are consistent with abnormalities in glucose metabolism. These data show that direct Akt inhibition may be useful in cancer therapy, but significant metabolic toxicities are likely dose limiting.

Keywords:
  • Signal transduction
  • PKB
  • Akt
  • PTEN
  • mTOR
  • p70s6k
  • TSC1
  • TSC2
  • FOXO
  • FKHRL

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • Grant support: R. de Jong is currently at the Syrrx, Inc., 10410 Science Center Drive, San Diego, CA 92121.

    • Accepted April 11, 2005.
    • Received January 6, 2005.
    • Revision received March 16, 2005.
  • American Association for Cancer Research
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Molecular Cancer Therapeutics: 4 (6)
June 2005
Volume 4, Issue 6
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Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo
Yan Luo, Alexander R. Shoemaker, Xuesong Liu, Keith W. Woods, Sheela A. Thomas, Ron de Jong, Edward K. Han, Tongmei Li, Vincent S. Stoll, Jessica A. Powlas, Anatol Oleksijew, Michael J. Mitten, Yan Shi, Ran Guan, Thomas P. McGonigal, Vered Klinghofer, Eric F. Johnson, Joel D. Leverson, Jennifer J. Bouska, Mulugeta Mamo, Richard A. Smith, Emily E. Gramling-Evans, Bradley A. Zinker, Amanda K. Mika, Phong T. Nguyen, Tilman Oltersdorf, Saul H. Rosenberg, Qun Li and Vincent L. Giranda
Mol Cancer Ther June 1 2005 (4) (6) 977-986; DOI: 10.1158/1535-7163.MCT-05-0005

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Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo
Yan Luo, Alexander R. Shoemaker, Xuesong Liu, Keith W. Woods, Sheela A. Thomas, Ron de Jong, Edward K. Han, Tongmei Li, Vincent S. Stoll, Jessica A. Powlas, Anatol Oleksijew, Michael J. Mitten, Yan Shi, Ran Guan, Thomas P. McGonigal, Vered Klinghofer, Eric F. Johnson, Joel D. Leverson, Jennifer J. Bouska, Mulugeta Mamo, Richard A. Smith, Emily E. Gramling-Evans, Bradley A. Zinker, Amanda K. Mika, Phong T. Nguyen, Tilman Oltersdorf, Saul H. Rosenberg, Qun Li and Vincent L. Giranda
Mol Cancer Ther June 1 2005 (4) (6) 977-986; DOI: 10.1158/1535-7163.MCT-05-0005
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Molecular Cancer Therapeutics
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