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


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Antonio Garcia-Trinidad1,Steve Durant2,Lucy Riches1,Jacqueline Fok1,Tom Hunt1,Kurt Pike2,Joanne Wilson1,Aaron Smith1,Nicola Colclough1,Venkatesh Pilla Reddy2,Andrew Sykes1,Annika Janefeldt1,Peter Johnström1,Stephanie Ling1,Jonathan Orme1,Jonathan Stott1,Caroline Roberts1,Ian Barrett1,Gemma Jones1,Martine Roudier1,Andrew Pierce1,Kristoffer Valerie3,Martin Pass1
1Astrazeneca,2AstraZeneca,3Commonwealth University

Abstract

Background

Poor survival rates of patients with tumours arising from or disseminating into the brain are attributed to an inability to excise all tumour tissue if operable, a lack of blood-brain barrier (BBB) penetration of chemotherapies/targeted agents and tumour radio-/chemo-resistance. ATM orchestrates the cellular DDR to DNA damage induced by ionising radiation (IR). ATM genetic ablation or pharmacological inhibition results in tumour cell hypersensitivity to IR. We report the primary pharmacology of the clinical-grade, exquisitely potent, highly selective, orally bioavailable ATM inhibitor AZD1390 specifically optimised for BBB penetration confirmed in macaque brain PET imaging of 11C-labelled AZD1390 (Kp,uu: 0.33). AZD1390 blocks ATM-dependent DDR, combines with radiation to induce G2 cell-cycle accumulation, micronuclei and apoptosis and radiosensitises glioma and lung cancer cells with p53-mutant glioma cells being generally more radiosensitised than wild type. In in vivo orthotopic syngeneic and PDX GBM and lung-brain metastatic models, AZD1390 dosed with daily fractions of IR (whole-brain or stereotactic) significantly induced tumour regressions and increased animal survival. A PK-PD-efficacy relationship was established by correlating free-brain concentrations, tumour pATM/pRad50 inhibition, apoptosis, tumor regression and survival. Based on this data, AZD1390 is now in AstraZeneca-led Phase 1 clinical trials as a radio-sensitiser in central nervous system malignancies.