Capivasertib

1143532-39-1

C21H25ClN6O2

DMSO : >= 21.5 mg/mL (50.13 mM)

PI3K/Akt/mTOR; Autophagy

Capivasertib (AZD5363) is a potent pan-AKT kinase inhibitor with IC₅₀ of 3, 7 and 7 nM for Akt1, Akt2 and Akt3, respectively. IC50 & Target: IC50: 3 nM (Akt1), 7 nM (Akt2), 7 nM (Akt3), 6 nM (p70S6K), 7 nM (PKA), 60 nM (ROCK2)^[1] In Vitro: Capivasertib, a novel pyrrolopyrimidine-derived compound, inhibits all AKT isoforms with a potency of 10 nM or less and inhibits phosphorylation of AKT substrates in cells with a potency of approximately 0.3 to 0.8 uM. Capivasertib inhibits phosphorylation of these substrates with an IC₅₀ value of 0.06 to 0.76 uM in the 3 cell lines. Capivasertib effectively inhibits phosphorylation of S6 and 4E-BP1 in these cell lines, whereas it increases phosphorylation of AKT at both ser⁴⁷³ and thr³⁰⁸. In BT474c cells, Capivasertib induces FOXO3a nuclear translocation with EC₅₀ value of 0.69 uM; a concentration of 3 uM is sufficient to almost completely localize FOXO3a to the nucleus. AZD5363Capivasertibhibitor MK-2206 is much less active (IC₅₀>30 uM)^[1]. In Vivo: Oral dosing of Capivasertib (AZD5363) to nude mice causes dose- and time-dependent reduction of PRAS40, GSK3beta, and S6 phosphorylation in BT474c xenografts (PRAS40 phosphorylation EC₅₀ ca.0.1 uM 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 Capivasertib caused dose-dependent growth inhibition of xenografts derived from various tumor types, including HER2⁺ breast cancer models. Capivasertib also significantly enhances the antitumor activity of RP-56976 and GW572016 in breast cancer xenografts^[1].