Orally Bioavailable and Blood-Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice.

摘要: Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A major impediment for clinical implementation is that current inhibitors have limited central nervous system (CNS) bioavailability; thus, goal was identify ATM (ATMi) with improved CNS penetration. Drug screens and refinement lead compounds identified AZ31 AZ32. The were then tested in vivo efficacy impact on healthy brain. Both AZ32 blocked damage radiosensitized GBM cells vitro AZ32, enhanced blood-brain barrier (BBB) penetration, highly efficient as radiosensitizer syngeneic human, orthotopic mouse glioma model compared AZ31. Furthermore, human cell lines expressing mutant p53 or having checkpoint-defective mutations particularly sensitive ATMi radiosensitization. mechanism this effect involves a propensity undergo mitotic catastrophe relative wild-type p53. In vivo, apoptosis >6-fold higher brain after exposure low-dose radiation. first oral bioavailability shown radiosensitize survival models. These findings support development clinical-grade, BBB-penetrating treatment GBM. Importantly, because many GBMs defective signaling, use an concurrent standard expected be cancer-specific, increase therapeutic ratio, maintain full at lower radiation doses. Mol Cancer Ther; 17(8); 1637-47. ©2018 AACR.