AZ31

AZ31 is a a potent, highly selective, and orally active ATM inhibitor with an IC50 of <1.2 nM for ATM enzyme, and an IC50 of 46 nM for ATM in cell. AZ31 shows excellent selectivity over ATR (>500-fold) and excellent PIKK-family selectivity and pan-kinase selectivity. AZ31 is a potent radiosensitizer in vitro, it can be used for the research of cancer[1].

Research Areas >> Cancer

Signaling Pathways >> Cell Cycle/DNA Damage >> ATM/ATR

Signaling Pathways >> PI3K/Akt/mTOR >> ATM/ATR

ATM:1.2 nM (IC50)

ATM:46 nM (IC50, in cell)

AZ31 (0.3-3 μM; 1 h) affects phosphorylation of a panel of ATM targets[1]. AZ31 (10 μM; 1 h) affects stabilization of p53 in H2228 lung cancer cells after radiation[1]. Western Blot Analysis[1] Cell Line: Human glioma cell line Concentration: 0.3, 1 and 3 μM Incubation Time: 1 hour Result: Blocked phosphorylation of p53-S15, KAP1-S824, and ATM auto-phosphorylation at S1981. Western Blot Analysis[1] Cell Line: H460 and mutant p53 H2228 cell lines Concentration: 10 μM Incubation Time: 1 hour Result: Destabilized p53 of mutant p53 but not wild-type after radiation.

AZ31 (50-100 mg/kg; p.o. twice a day) shows low brain coverage[1]. Animal Model: Nude mice[1] Dosage: 50 and 100 mg/kg Administration: Oral gavage; 50 and 100 mg/kg twice a day Result: Exhibited exposure over IC50 at 0.046 μM in brain only for 2-3 hours.

[1]. Karlin J, et al. Orally Bioavailable and Blood-Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice. Mol Cancer Ther. 2018 Aug;17(8):1637-1647.