Ataxia telangiectasia mutated (ATM) protein is a critical kinase that responds to DNA double-strand breaks (DSB) and reactive oxygen species (ROS) induced by cellular exposures to ionizing radiation (IR) and certain intrinsic stimuli. ATM is an ATP-dependent phosphatidylinositol 3-kinase-related kinase (PIKK) serine/threonine protein kinase related to ATR, DNA-PKcs, mTOR, SMG1, and the nonenzymatic TRRAP within this enzyme family[1]. AZ32 is an orally bioavailable and blood-brain barrier-penetrating ATM inhibitor with an IC50 of <6.2 nM for ATM enzyme, and an IC50 of 0.31 μM for ATM in cell[1]. AZ32 blocked the DNA damage response and radiosensitized GBM cells in vitro[1]. AZ32, with enhanced blood–brain barrier (BBB) penetration, was highly efficient in vivo as radiosensitizer in syngeneic and human, orthotopic mouse glioma model. In vivo, apoptosis was >6-fold higher in tumor relative to healthy brain after exposure to AZ32 and low-dose radiation. AZ32 is the first ATMi with oral bioavailability shown to radiosensitize glioma and improve survival in orthotopic mouse models. Following a single oral dose of AZ32 (200 mg/kg) in mice, the free-brain concentrations of AZ32 are in excess of the cellular IC50 for approximately 22 hours[1].
AZ32 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human glioma U87 cells
Human glioma U87 cells
16 h
p53 knockdown sensitized U87 cells to AZ32 radiosensitization, resulting in higher rates of mitotic catastrophe.
Mol Cancer Ther. 2018 Aug;17(8):1637-1647.
Human glioma U1242 cells
Human glioma U1242 cells
48 h
AZ32 and radiation treatment led to increased centrosomes and anaphase bridges, indicating elevated mitotic failure.
Mol Cancer Ther. 2018 Aug;17(8):1637-1647.
S1-M1-80 cells
S1-M1-80 cells
72 h
AZ32 does not alter the protein expression of ABCG2
Front Oncol. 2021 May 20;11:680663.
Mouse glioma GL261 cells
Mouse glioma GL261 cells
1 h
AZ32 blocked the phosphorylation of p53 and KAP-1 post-radiation and sensitized GL261 cells to radiation in a clonogenic survival assay.
Mol Cancer Ther. 2018 Aug;17(8):1637-1647.
DU145 cells
DU145 cells
48 h
Evaluate the effect of AZ32 on AR-negative prostate cancer cells, results showed that AZ32 combined with selinexor enhanced apoptosis
FASEB J. 2025 Jan 31;39(2):e70342.
LNCaP cells
LNCaP cells
48 h
Evaluate the effect of AZ32 on prostate cancer cell growth and survival, results showed that AZ32 combined with selinexor enhanced apoptosis and γ-H2AX accumulation
FASEB J. 2025 Jan 31;39(2):e70342.
AZ32 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57bl6 mice
GL261/luc-red intracranial glioma model
Oral
200 mg/kg
Once daily for 5 days
AZ32 significantly prolonged the survival of mice with intracranial tumors, with more than half of the mice apparently cured compared to radiation alone.
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