Preclinical pharmacology of AZD5363, an inhibitor of AKT: Pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background

Barry R. Davies, Hannah Greenwood, Phillippa Dudley, Claire Crafter, De Hua Yu, Jingchuan Zhang, Jing Li, Beirong Gao, Qunsheng Ji, Juliana Maynard, Sally Ann Ricketts, Darren Cross, Sabina Cosulich, Christine C. Chresta, Ken Page, James Yates, Clare Lane, Rebecca Watson, Richard Luke, Donald OgilvieMartin Pass

Research output: Contribution to journalArticlepeer-review

Abstract

AKT is a key node in the most frequently deregulated signaling network in human cancer. AZD5363, a novel pyrrolopyrimidine-derived compound, inhibited all AKT isoforms with a potency of 10 nmol/L or less and inhibited phosphorylation of AKT substrates in cells with a potency of approximately 0.3 to 0.8 mmol/L. AZD5363 monotherapy inhibited the proliferation of 41 of 182 solid and hematologic tumor cell lines with a potency of 3 mmol/L or less. 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 EC 50 ∼ 0.1 μmol/L total plasma exposure), reversible increases in blood glucose concentrations, and dose-dependent decreases in 2[18F]fluoro-2-deoxy-D-glucose ( 18F-FDG) uptake in U87-MG xenografts. Chronic oral dosing of AZD5363 caused dose-dependent growth inhibition 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. ©2012 AACR.
Original languageEnglish
Pages (from-to)873-887
Number of pages14
JournalMolecular Cancer Therapeutics
Volume11
Issue number4
DOIs
Publication statusPublished - 2012

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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