Biological Activity
AZD8835 is a potent and selective inhibitor of PI3Kα and PI3Kδ with IC50s of 6.2 and 5.7 nM, respectively.
In Vitro
The selectivity profile of AZD8835 (Compound 25) among the class I PI3K isoforms is tested in enzyme and cell based assays. At the enzyme level, AZD8835 is a potent mixed inhibitor of PI3Kα (IC50 6.2 nM) and PI3Kδ (IC50 5.7 nM), with selectivity against PI3Kβ (IC50 431 nM) and PI3Kγ (IC50 90 nM). AZD8835 is also a potent inhibitor of the commonly occurring PI3Kα mutants, PI3Kα- E545K (IC50 6 nM) and PI3Kα-H1047R (IC50 5.8 nM). In cell-based assays assessing the ability to inhibit Akt phosphorylation, AZD8835 is a potent inhibitor in cells sensitive to PI3Kα inhibition (IC50 57 nM in PIK3CA mutant human breast ductal carcinoma BT474 cell line) and in cells sensitive to PI3Kδ inhibition (IC50 49 nM in Jeko-1 B cell line, but not to cells sensitive to PI3Kβ inhibition (IC50 3.5 μM in PTEN null breast adenocarcinoma MDA-MB-468 cells) or to PI3Kγ inhibition (IC50 530 nM in monocytic RAW264 cell line)[1].
In Vivo
AZD8835 (Compound 25) displays good solubility, good permeability and low turnover in hepatocytes from various species. As expected from the in vitro data, low in vivo clearance associated with high bioavailability is seen in both rat and dog. AZD8835 shows high exposure following oral administration to SCID mice (AUC: 137 μM.h and Cmax 34 μM at 50 mg/kg p.o.) and is selected for further in vivo evaluation. In a pharmacodynamic experiment following chronic oral dosing (25 mg/kg b.i.d. or 6 mg/kg b.i.d. of AZD8835) in nude mice bearing mutant H1047R PI3Kα SKOV-3 tumour xenografts, target modulation is assessed by measuring Akt phosphorylation levels at Ser473 at 30 minutes and 8 hours. At both doses, strong inhibition of Akt phosphorylation is observed at the 30 minute timepoint. At 8 hours, significant inhibition is still seen at the 25 mg/kg dose, whereas no inhibition is seen at the lower dose of 6 mg/kg, consistent with the lower plasma concentrations observed[1].
References & source
Published experimental findings depend on the model and assay conditions. They do not guarantee equivalent performance in every application. For laboratory research use only.
