Preclinical Pharmacology of AZD5363, an Orally Bioavailable Inhibitor of AKT: Pharmacodynamics, Antitumor Activity and Correlation of Monotherapy Activity with Genetic Background
Menée in vitro et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un composé appelé ADF5363, un inhibiteur de la voie AKT, seul et en combinaison avec du docétaxel, du lapatinib ou du trastuzumab
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.
http://mct.aacrjournals.org/content/early/2012/01/28/1535-7163.MCT-11-0824-T.abstract 2012