Targeting Glioblastoma with AZD1390: A BBB-Crossing ATM Kinase Inhibitor

Glioblastoma multiforme (GBM) is a primary brain tumor with a grim prognosis due to its invasive nature and resistance to conventional therapies, which include surgery, radiotherapy, and chemotherapy. The median survival for GBM patients is only 12-15 months. The tumor's aggressiveness is partly due to its ability to infiltrate surrounding brain tissue, its inherent resistance to chemotherapy and radiation, and the blood-brain barrier (BBB), which hinders the delivery of chemotherapeutic agents.

Ataxia telangiectasia mutant (ATM), a protein kinase from the PIKK family, is pivotal in the DNA damage response, particularly in response to double-strand breaks (DSB). ATM activation is key to DNA repair, cell cycle regulation, and cell survival or death pathways. DSBs can occur due to chemotherapy or radiation exposure. Targeting ATM with inhibitors to enhance the sensitivity of tumors to treatment is a promising therapeutic strategy.

The development of a drug that can penetrate the BBB is a significant challenge. AZD1390 is a novel ATM inhibitor that has been identified as a potential treatment for brain tumors. It is an oral medication with the ability to cross the BBB and has been shown to be highly potent against ATM in cells (IC50 = 0.78 nM), with a high degree of selectivity over related enzymes and a broad range of kinases.

AZD1390 has demonstrated excellent oral bioavailability in preclinical models and has been confirmed to cross the BBB in non-human primates. It has not been found to be a substrate for human efflux transporters. In orthotopic xenograft models, significant tumor regression and increased survival have been observed with the combination of AZD1390 and radiotherapy, compared to radiotherapy alone.

The findings indicate that ATM inhibitors like AZD1390 could offer a new therapeutic approach for treating brain cancers. AZD1390 is currently in the early stages of clinical evaluation. The study was presented by Kurt G. Pike at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in 2017.