Mechanism of action: Brain penetrant Ataxia telangiectasia mutant (ATM) kinase inhibitor

Preclinical pharmacology

AZD1390 is a highly potent brain penetrant ATM (Ataxia telangiectasia mutant) 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.

Additional Information

Clinical Trials for this compound

See all of the Clinical Trials currently associated with this compound:

Publications for this compound

Durant S. T. et al. Sci Adv. 2018 Jun; 4(6): eaat1719.

Gene information from the NCBi

This compound works on the following genes: