Capivasertib (AZD5363) is a potent, selective and orally bioavailable inhibitor of pan-Akt kinases with IC50 of <10 nM.
AZD5363 exhibits similar potency against P70S6K and PKA (IC50=6 and 7 nM) but a lower potency against the Rho kinases ROCK1 and ROCK2.
AZD5363 inhibited phosphorylation of AKT substrates in cells with a potency of 0.3-0.8 uM.
AZD5363 inhibited the proliferation of 41 of 182 solid and hematologic tumor cell lines with IC50 of <3 uM.
Oral dosing of AZD5363 (100 and 200mg/kg twice daily) reduces 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 ((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.
