capivasertib

Description: Capivasertib (formerly known as AZD5363), a novel pyrrolopyrimidine-derived compound, is a potent, orally available pan-AKT kinase inhibitor with IC50 of 3, 7 and 7 nM for Akt1, Akt2 and Akt3, respectively. AKT is a key node in the most frequently deregulated signaling network in human cancer. AZD5363 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 umol/L. AZD5363 monotherapy inhibited the proliferation of 41 of 182 solid and hematologic tumor cell lines with a potency of 3 umol/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, GSK3beta, and S6 phosphorylation in BT474c xenografts (PRAS40 phosphorylation EC(50) ca. 0.1 umol/L total plasma exposure), reversible increases in blood glucose concentrations, and dose-dependent decreases in 218Ffluoro-2-deoxy-D-glucose ((18)F-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.

References: Mol Cancer Ther. 2012 Apr; 11(4):873-87.