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Molecular Cancer Therapeutics
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Research Article

Preclinical Pharmacology of AZD5363, an Orally Bioavailable Inhibitor of AKT: Pharmacodynamics, Antitumor Activity and Correlation of Monotherapy Activity with Genetic Background

Barry R Davies, Hannah Greenwood, Philippa Dudley, Claire Crafter, De-Hua Yu, Jingchuan Zhang, Jing Li, Beirong Gao, Qunsheng Ji, Juliana Maynard, Sally-Ann Ricketts, Darren Cross, Sabina C Cosulich, Christine M Chresta, Ken Page, James Yates, Clare Lane, Rebecca Watson, Richard Luke, Donald J Ogilvie and Martin Pass
Barry R Davies
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  • For correspondence: Barry.Davies@astrazeneca.com
Hannah Greenwood
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Philippa Dudley
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Claire Crafter
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De-Hua Yu
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Jingchuan Zhang
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Jing Li
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Beirong Gao
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Qunsheng Ji
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Juliana Maynard
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Sally-Ann Ricketts
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Darren Cross
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Sabina C Cosulich
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Christine M Chresta
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Ken Page
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James Yates
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Clare Lane
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Rebecca Watson
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Richard Luke
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Donald J Ogilvie
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Martin Pass
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DOI: 10.1158/1535-7163.MCT-11-0824-T
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Abstract

AKT is a key node in the most frequently de-regulated signaling network in human cancer. AZD5363, a novel pyrrolopyrimidine derived compound, inhibited all AKT isoforms with a potency of <10 nM, and inhibited phosphorylation of AKT substrates in cells with a potency of ~0.3 to 0.8 µM. AZD5363 monotherapy inhibited the proliferation of 41/182 solid and hematologic tumor cell lines with a potency of <3 µM. Cell lines derived from breast cancers showed the highest frequency of sensitivity. There was a significant relationship between the presence of PIK3CA and/or PTEN mutations and sensitivity to AZD5363, and between RAS mutations and resistance. Oral dosing of AZD5363 to nude mice caused dose- and time-dependent reduction of PRAS40, GSK3β and S6 phosphorylation in BT474c xenografts (PRAS40 phosphorylation EC50 ~0.1 µM total plasma exposure), reversible increases in blood glucose concentrations and dose-dependent decreases in fluorodeoxyglucose (FDG) uptake in U87-MG xenografts. Chronic oral dosing of AZD5363 caused dose-dependent inhibition of the growth of xenografts derived from various tumor types, including HER2+ breast cancer models that are resistant to trastuzumab. AZD5363 also significantly enhanced the antitumor activity of docetaxel, lapatinib and trastuzumab in breast cancer xenografts. It is concluded that AZD5363 is a potent inhibitor of AKT with pharmacodynamic activity in vivo, has potential to treat a range of solid and hematologic tumors as monotherapy or a combinatorial agent, and has potential for personalized medicine based on the genetic status of PIK3CA, PTEN and RAS. AZD5363 is currently in phase I clinical trials.

  • Received October 14, 2011.
  • Revision received January 6, 2012.
  • Accepted January 20, 2012.
  • Copyright © 2012, American Association for Cancer Research.
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This OnlineFirst version was published on January 31, 2012
doi: 10.1158/1535-7163.MCT-11-0824-T

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Preclinical Pharmacology of AZD5363, an Orally Bioavailable Inhibitor of AKT: Pharmacodynamics, Antitumor Activity and Correlation of Monotherapy Activity with Genetic Background
Barry R Davies, Hannah Greenwood, Philippa Dudley, Claire Crafter, De-Hua Yu, Jingchuan Zhang, Jing Li, Beirong Gao, Qunsheng Ji, Juliana Maynard, Sally-Ann Ricketts, Darren Cross, Sabina C Cosulich, Christine M Chresta, Ken Page, James Yates, Clare Lane, Rebecca Watson, Richard Luke, Donald J Ogilvie and Martin Pass
Mol Cancer Ther January 31 2012 DOI: 10.1158/1535-7163.MCT-11-0824-T

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Preclinical Pharmacology of AZD5363, an Orally Bioavailable Inhibitor of AKT: Pharmacodynamics, Antitumor Activity and Correlation of Monotherapy Activity with Genetic Background
Barry R Davies, Hannah Greenwood, Philippa Dudley, Claire Crafter, De-Hua Yu, Jingchuan Zhang, Jing Li, Beirong Gao, Qunsheng Ji, Juliana Maynard, Sally-Ann Ricketts, Darren Cross, Sabina C Cosulich, Christine M Chresta, Ken Page, James Yates, Clare Lane, Rebecca Watson, Richard Luke, Donald J Ogilvie and Martin Pass
Mol Cancer Ther January 31 2012 DOI: 10.1158/1535-7163.MCT-11-0824-T
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