AZD1390
Preclinical pharmacology
AZD1390 is a highly potent, brain penetrant ataxia telangiectasia mutant (ATM) kinase inhibitor that blocks ATM-dependent signaling and repair of DNA double strand breaks (DSBs) in the genome. AZD1390 therefore exhibits powerful activity in combination with agents such as irradiation and chemotherapies that induce DSBs. ATM inhibition may also generate an exploitable DDR dependency against tumour cells with other DDR pathway defects.
AZD1390 is an ATP-competitive kinase inhibitor with a cellular IC50 of 0.78 nM and is highly selective against other PIKKs including ATR, DNAPK, and mTOR. AZD1390 hyper sensitises a wide range of cancer cells to radiation in vitro, blocks the DDR to DSBs in cells and results in tumour regressions and survival improvement in orthotopic brain tumour models in vivo. AZD1390 establishes a PK-PD-efficacy relationship by linking dose-dependent plasma and brain concentrations to target engagement (pRAD50) and phenotypic tumour anti-proliferation and cell death markers.
AZD1390 exhibits significant CNS penetration with Kpu,u values of 0.04 (mouse), 0.17 (rat), and 0.33 (cynomolgus monkey).
Safety and tolerability
The toxicology of AZD1390 has been evaluated in studies of up to 1-month duration in rats and dogs and the principal target organs for toxicity were identified as the male reproductive organs, lymphoreticular system, central nervous system, skeletal muscle, lungs and pancreas. In addition, increases in heart weight were observed, and minor effects on the mammary gland and kidney.
Areas of interest
- to include exploration of combination treatment with double strand break including agents in solid tumour indications where there is a strong scientific, translational, or clinical rationale to target ATM inhibition
- Proposals will be prioritized accordingly based on scientific merit and fit with the core development program.
Mechanism of Action
Brain penetrant Ataxia telangiectasia mutant (ATM) kinase inhibitor
Original Therapeutic Area
Oncology
CNS Penetrant
Yes
Route of administration
Oral
Modality
Small Molecule
Additional Information
1. Durant ST., et al. (2018).
The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models. Sci Adv. 2018 Jun 20;4(6):eaat1719. doi: 10.1126/sciadv.aat1719. PMID: 29938225; PMCID: PMC6010333.