AZ32

AZ32 blocks the DNA damage response (DDR) and radiosensitized GBM cells in vitro. AZ32 shows moderate potency against ATM in cell (IC50 = 0.31 μM) and adequate selectivity over ATR, while also having high cell permeability^[1].

AZ32, with enhanced blood-brain barrier (BBB) penetration, was highly efficient in vivo as radiosensitizer in syngeneic and human, orthotopic mouse glioma model compared with AZ31. 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 was in excess of the cellular IC50 for approximately 22 hr. AZ32 has enhanced BBB penetration at 8.7-fold and improved brain coverage over AZ31 but with reduced ATM selectivity^[1].

• Cell lines

  U1242 cells

• Concentrations

  3 μM

• Incubation Time

  48 h

• Method

  Human glioma U1242 cells were treated with AZ32 (3 μM) and radiation (2 Gy) or left untreated. At 48 hrs the cells were fixed and processed for ICC using anti-γ-tubulin (centrosomes) and -α-tubulin (microtubules). Cells were counterstained with DAPI to visualize nuclei.

• Animal Models

  orthotopic GL261 glioma model (GL261/luc-red cells intracranially injected into C57bl6 mice)

• Dosages

  200 mg/kg

• Administration

  p.o.