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

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.