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Molecular Cancer Therapeutics
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Research Articles: Therapeutics, Targets, and Development

Discovery of a novel class of AKT pleckstrin homology domain inhibitors

Daruka Mahadevan, Garth Powis, Eugene A. Mash, Benjamin George, Vijay M. Gokhale, Shuxing Zhang, Kishore Shakalya, Lei Du-Cuny, Margareta Berggren, M. Ahad Ali, Umasish Jana, Nathan Ihle, Sylvestor Moses, Chloe Franklin, Satya Narayan, Nikhil Shirahatti and Emmanuelle J. Meuillet
Daruka Mahadevan
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Garth Powis
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Eugene A. Mash
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Benjamin George
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Vijay M. Gokhale
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Shuxing Zhang
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Kishore Shakalya
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Lei Du-Cuny
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Margareta Berggren
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M. Ahad Ali
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Umasish Jana
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Nathan Ihle
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Sylvestor Moses
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Chloe Franklin
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Satya Narayan
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Nikhil Shirahatti
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Emmanuelle J. Meuillet
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DOI: 10.1158/1535-7163.MCT-07-2276 Published September 2008
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Abstract

AKT, a phospholipid-binding serine/threonine kinase, is a key component of the phosphoinositide 3-kinase cell survival signaling pathway that is aberrantly activated in many human cancers. Many attempts have been made to inhibit AKT; however, selectivity remains to be achieved. We have developed a novel strategy to inhibit AKT by targeting the pleckstrin homology (PH) domain. Using in silico library screening and interactive molecular docking, we have identified a novel class of non–lipid-based compounds that bind selectively to the PH domain of AKT, with “in silico” calculated KD values ranging from 0.8 to 3.0 μmol/L. In order to determine the selectivity of these compounds for AKT, we used surface plasmon resonance to measure the binding characteristics of the compounds to the PH domains of AKT1, insulin receptor substrate-1, and 3-phosphoinositide–dependent protein kinase 1. There was excellent correlation between predicted in silico and measured in vitro KDs for binding to the PH domain of AKT, which were in the range 0.4 to 3.6 μmol/L. Some of the compounds exhibited PH domain–binding selectivity for AKT compared with insulin receptor substrate-1 and 3-phosphoinositide–dependent protein kinase 1. The compounds also inhibited AKT in cells, induced apoptosis, and inhibited cancer cell proliferation. In vivo, the lead compound failed to achieve the blood concentrations required to inhibit AKT in cells, most likely due to rapid metabolism and elimination, and did not show antitumor activity. These results show that these compounds are the first small molecules selectively targeting the PH domain of AKT. [Mol Cancer Ther 2008;7(9):2621–32]

Keywords:
  • AKT
  • Pleckstrin homology domain
  • Inhibitor
  • PDK1
  • IRS1
  • Drug design

Footnotes

  • Grant support: RO1 CA 061015 and P30 CA 23074 from the National Cancer Institute (G. Powis) and by grant ABRC no. 9010 from the Arizona Biomedical Research Commission (E.J. Meuillet).

  • 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.

  • Note: D. Mahadevan and G. Powis: both authors participated equally in the work presented in this publication.

    • Accepted May 14, 2008.
    • Received November 13, 2007.
    • Revision received April 14, 2008.
  • American Association for Cancer Research
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Molecular Cancer Therapeutics: 7 (9)
September 2008
Volume 7, Issue 9
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Discovery of a novel class of AKT pleckstrin homology domain inhibitors
Daruka Mahadevan, Garth Powis, Eugene A. Mash, Benjamin George, Vijay M. Gokhale, Shuxing Zhang, Kishore Shakalya, Lei Du-Cuny, Margareta Berggren, M. Ahad Ali, Umasish Jana, Nathan Ihle, Sylvestor Moses, Chloe Franklin, Satya Narayan, Nikhil Shirahatti and Emmanuelle J. Meuillet
Mol Cancer Ther September 1 2008 (7) (9) 2621-2632; DOI: 10.1158/1535-7163.MCT-07-2276

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Discovery of a novel class of AKT pleckstrin homology domain inhibitors
Daruka Mahadevan, Garth Powis, Eugene A. Mash, Benjamin George, Vijay M. Gokhale, Shuxing Zhang, Kishore Shakalya, Lei Du-Cuny, Margareta Berggren, M. Ahad Ali, Umasish Jana, Nathan Ihle, Sylvestor Moses, Chloe Franklin, Satya Narayan, Nikhil Shirahatti and Emmanuelle J. Meuillet
Mol Cancer Ther September 1 2008 (7) (9) 2621-2632; DOI: 10.1158/1535-7163.MCT-07-2276
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