Biochem/physiol Actions

AZ32 is an orally active, potent and selective ataxia telangiectasia mutated (ATM) kinase inhibitor (IC₅₀ ﹤6.2 nM; DNA-PK & PI3Ka IC₅₀ =4.6 µM, hERG IC₅₀ = 17.6 µM) with good aqueous solubility (24 µM) and blood-brain barrier (BBB) permeability in mice (free brain/plasma ratio = 0.26; 200 mg/kg p.o.). AZ32 exhibits radiosensitizing efficacy in human & murine glioma cultures by blocking radiation-induced DNA damage response (ATM pS1981 IC₅₀ = 310 nM; 100% blockage of KAP1 pS824 & p53 pS15 at 300 nM; T98G cells). AZ32 (200 mg/kg/day p.o.) improves whole-head irradiation treatment survival rate among mice with brain GL261 tumors or NCI-H2228 NSCLC metastases in vivo.