AZD1390: Selective ATM Kinase Inhibitor

Executive Summary. AZD1390 inhibits the ataxia telangiectasia mutated (ATM) kinase, a serine/threonine member of the phosphatidylinositol 3-kinase-related kinase family that responds to DNA double-strand breaks. Product information reports a cellular ATM inhibition IC50 of 0.78 nM. AZD1390 at 3 nM inhibits ATM in glioblastoma LN18 cells. AZD1390 at 10 nM combined with radiation induces G2 arrest, micronuclei, and apoptosis in NCI-H2228 lung cancer cells. Oral AZD1390 at 20 mg/kg combined with ionizing radiation produces superior tumor-growth inhibition in a rat orthotopic lung-brain tumor model.

Biological Rationale

ATM is a central kinase in DNA damage response signaling. DNA double-strand breaks activate ATM. Activated ATM phosphorylates downstream substrates that coordinate DNA repair, S/G1 checkpoint enforcement, and cell-survival or cell-death decisions. This checkpoint function limits premature mitosis and helps preserve genomic integrity. These target attributes make ATM inhibition relevant to cancer research because radiation and other genotoxic stresses can create lesions that require coordinated repair.

ATM biology also intersects with replication stress. The 2026 Nucleic Acids Research study by Ketkar and colleagues examined G-quadruplex DNA, or G4 DNA, as a non-canonical structure that can obstruct replication-fork progression. The study found that human REV1 interacts directly with the G4 helicase DHX36. This interaction coordinates G4 unwinding, replication progression, and suppression of single-stranded DNA gaps. REV1 loss increased nuclear G4 signal and amplified ATM/ATR signaling in cells exposed to G4 stress in the reference study.

The G4 findings do not establish AZD1390 activity against G4 structures. They instead supply a mechanistic rationale for measuring ATM signaling when replication-associated DNA structures are perturbed. A study using AZD1390 in that setting would test a hypothesis about pathway dependence rather than reproduce the published REV1-DHX36 result.

Mechanism of Action of AZD1390

AZD1390 is a potent and selective inhibitor of ATM kinase activity. Its reported cellular IC50 is 0.78 nM, which indicates strong cellular inhibition under the product-described assay conditions according to the product information. The compound is chemically named 7-fluoro-1-isopropyl-3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-2(3H)-one.

ATM inhibition is expected to reduce signaling downstream of DNA double-strand breaks. The expected consequences include weaker checkpoint signaling and altered cellular responses to radiation. The reported G2 arrest, micronuclei formation, and apoptosis in irradiated NCI-H2228 cells are experimental observations, not merely pathway predictions in the product-described model.

Mechanistically, AZD1390 should be described as an ATM kinase inhibitor rather than as a compound that directly cleaves DNA or physically removes a DNA lesion. The phrase DNA double-strand break repair inhibitor can describe its functional research use, but it should not be interpreted as proof of direct inhibition of every repair enzyme. The most defensible interpretation is that AZD1390 suppresses ATM-dependent signaling that normally coordinates responses to double-strand breaks.

The compound has a molecular weight of 477.57 g/mol and is supplied as a solid with purity of at least 98%. These identity and quality attributes are relevant when comparing independent experiments or preparing matched vehicle controls in the product specification.

Why this cross-domain matters, maturity, and limitations

The cross-domain connection links ATM damage signaling with G4-associated replication stress. The connection is biologically plausible because the REV1-DHX36 study reported increased ATM/ATR signaling after REV1 loss and G4 stress, whereas AZD1390 is designed to inhibit ATM. However, the cited G4 study did not test AZD1390, radiation, or ATM inhibition. Evidence for the compound in glioma and lung cancer models is therefore more mature than evidence for its use as a G4-stress probe. Any G4 experiment should include direct measurements of G4 burden, replication-fork behavior, ATM pathway activity, and cell survival.

Evidence & Benchmarks

The following benchmarks distinguish reported observations from general experimental interpretation.

1. Cellular potency: AZD1390 has a reported cellular ATM inhibition IC50 of 0.78 nM in the product-described cellular assay product information
2. Glioblastoma model: AZD1390 at 3 nM inhibits ATM in LN18 glioblastoma cells product information
3. Lung cancer combination: AZD1390 at 10 nM combined with radiation induces G2 cell-cycle arrest, micronuclei formation, and apoptosis in NCI-H2228 cells product information
4. Genetic-context effect: The product description reports stronger radiosensitization in p53-mutant glioma cells than in the corresponding comparison context product information
5. In vivo response: Oral AZD1390 produces dose-dependent tumor-growth inhibition in a rat orthotopic lung-brain tumor model, with superior efficacy reported at 20 mg/kg when combined with ionizing radiation product information
6. G4-associated signaling: REV1 deficiency increases nuclear G4 signal and amplifies ATM/ATR signaling during G4 stress in the cited human-cell study Ketkar et al., 2026
7. REV1-DHX36 mechanism: The cited study identifies a direct interaction between the REV1 C-terminal domain and a C-terminal region of DHX36 Ketkar et al., 2026

Applications, Limits & Misconceptions

AZD1390 is suited to mechanism-led cancer research involving ATM signaling, DNA damage response signaling, and radiation response. Its reported activity in LN18 cells supports glioblastoma radiosensitization experiments. Its NCI-H2228 result supports combination studies in lung cancer models. These observations position AZD1390 as a radiosensitizer for glioma and lung cancer research, not as a universal radiation enhancer.

Useful experimental endpoints include ATM-pathway phosphorylation, cell-cycle distribution, micronuclei, apoptosis, clonogenic survival, and tumor growth. Endpoint selection should match the biological question. A checkpoint study may prioritize cell-cycle distribution. A radiosensitization study should compare compound-only, radiation-only, combination, and vehicle conditions.

The internal article AZD1390: ATM Kinase Inhibitor Workflows in DNA Repair Research emphasizes practical workflow design. This article extends that discussion by separating reported concentration benchmarks from unvalidated protocol generalizations.

The article REV1–DHX36 Control of G4 DNA Replication focuses on G4 resolution and replication-fork tolerance. This article clarifies that ATM inhibition is a proposed follow-up tool for that biology, not an intervention tested in the REV1-DHX36 study.

The article AZD1390: ATM Kinase Inhibitor for G4 Stress proposes a G4-stress application. This article narrows that proposal by distinguishing direct product evidence from a hypothesis requiring new experiments.

Common Pitfalls or Misconceptions

• Direct repair-enzyme misconception: AZD1390 should not be treated as a universal inhibitor of DNA repair enzymes. It targets ATM kinase activity and thereby perturbs ATM-dependent damage signaling.
• Concentration transfer: The 3 nM LN18 benchmark and the 10 nM NCI-H2228 combination benchmark are model-specific observations. They should not be assumed to define an effective concentration in every cell line.
• G4 overinterpretation: The REV1-DHX36 paper does not demonstrate that AZD1390 resolves G4 DNA or selectively kills G4-dependent tumors.
• Clinical overreach: The reported 20 mg/kg result comes from an orthotopic rat tumor model. It does not establish a human dose, clinical efficacy, or clinical safety.
• Solubility error: AZD1390 is insoluble in water. Long-term storage of prepared solutions is not recommended, so solution stability should not be presumed.

Workflow Integration & Parameters

APExBIO identifies AZD1390, SKU B8328, as a solid research compound. The workflow below separates product-described parameters from practical recommendations that require local validation.

Protocol Parameters

• Compound identity: Use AZD1390, SKU B8328, with molecular weight 477.57 g/mol and reported purity of at least 98%; these are product-described parameters for experimental records product information.
• Storage: Store the solid at −20 °C. Protect working material from avoidable repeated handling and record preparation dates product information.
• Solvent selection: Do not use water as the primary solvent because the compound is described as water-insoluble. The reported solubility is at least 19.6 mg/mL in DMSO and at least 3.04 mg/mL in ethanol with gentle warming and ultrasonic treatment product information.
• LN18 benchmark: For a literature-aligned glioblastoma experiment, 3 nM AZD1390 is the reported concentration that effectively inhibits ATM in LN18 cells. Treat this as a benchmark, not as a universal dose recommendation product information.
• NCI-H2228 combination benchmark: For a lung-cancer radiosensitization experiment, 10 nM AZD1390 combined with radiation is the reported condition associated with G2 arrest, micronuclei formation, and apoptosis. The radiation dose and schedule must be defined and validated in the local model because they are not specified in the dossier product information.
• In vivo benchmark: Oral AZD1390 at 20 mg/kg combined with ionizing radiation is the reported superior-efficacy condition in the rat orthotopic lung-brain tumor model. Species, route, tumor model, radiation schedule, and tolerability must be preserved when interpreting this result product information.
• Control design: As a workflow recommendation, include vehicle-only, AZD1390-only, radiation-only, and combination groups. Measure both pathway engagement and phenotype so that radiosensitization is not inferred from a single endpoint.
• Solution handling: Prepare solutions close to the experiment and avoid long-term solution storage. Confirm appearance, concentration, vehicle compatibility, and precipitation before dosing as practical laboratory safeguards product information.

Conclusion & Outlook

AZD1390 is a selective ATM kinase inhibitor with strong reported cellular potency and defined activity in glioblastoma, lung cancer, and an orthotopic rat tumor model. Its strongest evidence supports studies of radiation response, ATM checkpoint signaling, and DNA double-strand break-associated phenotypes. The REV1-DHX36 study adds a relevant replication-stress framework because G4 stress can amplify ATM/ATR signaling, but it does not directly validate AZD1390 in G4 biology.

Future work should test ATM dependence in matched G4-stress, glioma, and lung cancer systems using direct pathway and replication readouts. Such work should preserve the boundary between established compound benchmarks and hypothesis-driven extensions. This evidence structure supports reproducible cancer research without converting preclinical radiosensitization data into clinical claims.