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Sci Adv. 2018 Jun 20;4(6):eaat1719. doi: 10.1126/sciadv.aat1719. eCollection 2018 Jun.

The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models.

Author information

1
Bioscience, Oncology Innovative Medicines and Early Development (IMED) Biotech Unit, AstraZeneca, Cambridge, UK.
2
Bioscience, Innovative Cancer Centre, Oncology IMED Biotech Unit, AstraZeneca, Shanghai, China.
3
Drug Metabolism and Pharmacokinetics, Innovative Cancer Centre, Oncology IMED Biotech Unit, AstraZeneca, Shanghai, China.
4
Chemistry, Oncology IMED Biotech Unit, AstraZeneca, Cambridge, UK.
5
Drug Metabolism and Pharmacokinetics, Oncology IMED Biotech Unit, AstraZeneca, Cambridge, UK.
6
Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
7
Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Karolinska Institutet, Stockholm, Sweden.
8
Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden.
9
Discovery Sciences, Oncology IMED Biotech Unit, AstraZeneca, Cambridge, UK.
10
Translational Sciences, Oncology IMED Biotech Unit, AstraZeneca, Cambridge, UK.
11
Department of Radiation Oncology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298-0058, USA.
12
Drug Safety and Metabolism, Oncology IMED Biotech Unit, AstraZeneca, Cambridge, UK.
13
Operations, AstraZeneca, Waltham, MA 02451, USA.
14
Projects, Oncology IMED Biotech Unit, AstraZeneca, Cambridge, UK.

Abstract

Poor survival rates of patients with tumors arising from or disseminating into the brain are attributed to an inability to excise all tumor tissue (if operable), a lack of blood-brain barrier (BBB) penetration of chemotherapies/targeted agents, and an intrinsic tumor radio-/chemo-resistance. Ataxia-telangiectasia mutated (ATM) protein orchestrates the cellular DNA damage response (DDR) to cytotoxic DNA double-strand breaks induced by ionizing radiation (IR). ATM genetic ablation or pharmacological inhibition results in tumor cell hypersensitivity to IR. We report the primary pharmacology of the clinical-grade, exquisitely potent (cell IC50, 0.78 nM), highly selective [>10,000-fold over kinases within the same phosphatidylinositol 3-kinase-related kinase (PIKK) family], orally bioavailable ATM inhibitor AZD1390 specifically optimized for BBB penetration confirmed in cynomolgus monkey brain positron emission tomography (PET) imaging of microdosed 11C-labeled AZD1390 (Kp,uu, 0.33). AZD1390 blocks ATM-dependent DDR pathway activity and combines with radiation to induce G2 cell cycle phase accumulation, micronuclei, and apoptosis. AZD1390 radiosensitizes glioma and lung cancer cell lines, with p53 mutant glioma cells generally being more radiosensitized than wild type. In in vivo syngeneic and patient-derived glioma as well as orthotopic lung-brain metastatic models, AZD1390 dosed in combination with daily fractions of IR (whole-brain or stereotactic radiotherapy) significantly induced tumor regressions and increased animal survival compared to IR treatment alone. We established a pharmacokinetic-pharmacodynamic-efficacy relationship by correlating free brain concentrations, tumor phospho-ATM/phospho-Rad50 inhibition, apoptotic biomarker (cleaved caspase-3) induction, tumor regression, and survival. On the basis of the data presented here, AZD1390 is now in early clinical development for use as a radiosensitizer in central nervous system malignancies.

PMID:
29938225
PMCID:
PMC6010333
DOI:
10.1126/sciadv.aat1719
[Indexed for MEDLINE]
Free PMC Article

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