A66

A66 is a highly specific and selective p110α inhibitor with an IC₅₀ of 32 nM. IC50 & Target: IC50: 32 nM (p110α), 30 nM (p110α E545K), 43 nM (p110α H1047R), 3480 nM (p110γ)^[1] In Vitro: A66 is a potent inhibitor of the wild-type and oncogenic forms of p110α but not other class-I PI3K isoforms^[1]. The p110α-specific inhibitor A66 (0.7 μM) induces a 75-80% reduction in focus formation by the highly transforming iSH2 mutants KS459delN, DKRMNS560del, and K379E. The p110α-specific inhibitor A66 reduced phosphorylation of Akt on T308 by all p85 mutants^[2]. In Vivo: The optimal dosing strategy for xenograft studies is determined by investigating the drug pharmacokinetics after a dose of 10 mg/kg of body weight by intraperitoneal injection in CD-1 mice. Despite a short half-life of only 0.42 h, the large C_max (8247 nM) of A66 S that is reached 30 min after dosing ensured that the AUC_0-inf (area under the curve from zero time to infinity) (6809 nM•h) is similar to that of BEZ-235 (7333 nM•h), which has a longer half-life of 2.73 h. Furthermore, the A66 on SK-OV-3 tumour tissue is tested using a single dose of 100 mg/kg of body weight to determine whether a long-lasting effect of the drug could be achieved on target tissues. These studies show that A66 causes a profound reduction in the phosphorylation of Akt/PKB and p70 S6 kinase, but not of ERK (extracellular-signal-regulated kinase), at both 1 and 6 h after dosing. Levels of A66 in plasma are determined to be 21.1±1.2 μM and 9.1±1.1 μM at 1 and 6 h after drug injection, whereas levels of A66 in the tumor are 22.7±2.1 μM and 16.0±1.3 μM at the same time points^[1].