AZD1390

AZD1390 is a potent and selective inhibitor of ataxia telangiectasia mutant (ATM) kinase, with IC50 value of 0.78 nM in cells [1]. 

ATM, a serine/threonine protein kinase from the phosphatidylinositol 3-kinase-related kinase family of protein kinases, plays an important role in the cellular DNA damage response signaling activated by DNA double-strand breaks. Activated ATM promotes DNA repair and S/G₁-cell cycle checkpoints to prevent premature mitosis, maintain genomic integrity, and promote appropriate cell survival or death pathways [1]. 

In LN18 GBM cells, AZD1390 at a concentration of 3 nM produced a strong inhibition of ATM. In NCI-H2228 cells, AZD1390 (10 nM) combined with radiation induced G₂ cell cycle phase accumulation, micronuclei, and apoptosis. Furthermore, AZD1390 at 10 nM radiosensitized glioma and lung cancer cell lines, with p53 mutant glioma cells generally being more radiosensitized than the wild type [2]. 

In a rat model of NCI-H2228 orthotopic lung-brain tumor, AZD1390 inhibited tumor growth in a dose-dependent manner, with marginal inhibition observed using AZD1390 (5 mg/kg) which was orally dosed an hour before each daily fraction of ionizing radiation (IR). Superior efficacy was observed dosing at 20 mg/kg once daily or twice daily in combination with the four daily fractions of IR. 

References:

[1]. Pike K G. Abstract A124: Discovery of the clinical candidate AZD1390: a high-quality, potent, and selective inhibitor of ATM kinase with the ability to cross the blood-brain barrier. Molecular Targets and Cancer Therapeutics, 2018, 17(1).

[2]. Durant S T, Zheng L, Wang Y, et al. The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models. Science Advances, 2018, 4(6): eaat1719.