Mechanism of action: ATM kinase inhibitor

Preclinical pharmacology

AZ32 inhibits ATM in enzyme (<6.2nM) and cellular (310nM) assays.

AZ32 radiosensitises GL261 cells in vitro and in vivo in orthotopic brain xenograft mouse models. AZ32 also efficacious in lung NCIH2228 orthotopic model in nude mice also dosed with daily 2.5Gy x 4 day fractions. In kinase selectivity screening, 4/124 Kinases were inhibited by >50% (JAK2:96%, ABL2: 56%, STK10: 53%, JAK3: 52%). Acceptable hERG IC50 of 17.6. Blood brain barrier penetration as measured by free brain:free plasma ratio (Kpuu) of 0.38 using mouse brain homogenate.

Formulation: 10% Ethanol 90% PEG200

Safety and tolerability

AZ32 is tolerated in C57Bl6 and Nude mice dosed orally at 200mg/kg which was efficacious in orthotopic mouse models.

Suitable for and exclusions

Preclinical proposals only. The compound structure is expected to be disclosed mid-2016.