AZD0156: Selective ATM Kinase Inhibitor for DNA Damage Response Research

Executive Summary: AZD0156 (B7822, CAS 1821428-35-6) is a potent, selective, orally bioavailable inhibitor of the ataxia-telangiectasia mutated (ATM) kinase, a key regulator of the DNA damage response (DDR) pathway. AZD0156 exhibits sub-nanomolar inhibition of ATM signaling with over 1000-fold selectivity versus other PIKK family kinases, making it suitable for targeted research applications (Huang et al., 2023). Preclinical studies show that AZD0156 enhances anticancer efficacy when combined with agents that induce DNA double-strand breaks. The compound is supplied by APExBIO with stringent quality control and >98% purity (APExBIO product page). Proper storage and handling are required for optimal experimental results. Insights into metabolic adaptation and checkpoint modulation provide new directions for translational cancer therapy research.

Biological Rationale

ATM kinase is a serine/threonine protein kinase in the PIKK family. It is central to the cellular response to DNA double-strand breaks (DSBs). ATM detects DSBs and initiates phosphorylation cascades that regulate DNA repair, cell cycle checkpoints, and apoptosis (Huang et al., 2023). Loss or inhibition of ATM function leads to genomic instability and increased susceptibility to tumorigenesis. ATM's role extends beyond DNA damage sensing; it modulates cellular metabolism and stress responses. In cancer, ATM is frequently deregulated, making it a promising target for synthetic lethality strategies and combination therapy research.

Mechanism of Action of AZD0156

AZD0156 is a small-molecule inhibitor designed to bind the ATP-binding pocket of ATM kinase, thereby blocking its catalytic activity. This inhibition disrupts downstream phosphorylation of key DDR effectors such as p53, CHK2, and H2AX. AZD0156 demonstrates sub-nanomolar IC₅₀ values in cellular assays, with >1000-fold selectivity over other PIKK kinases (e.g., ATR, DNA-PKcs) (APExBIO). Inhibition of ATM by AZD0156 impairs DSB repair, checkpoint activation, and regulation of cell cycle progression. This leads to increased sensitivity of tumor cells to genotoxic agents and potential synthetic lethal interactions in ATM-deficient or DDR-defective backgrounds.

Evidence & Benchmarks

• AZD0156 inhibits cellular ATM signaling with sub-nanomolar potency (IC₅₀ < 1 nM) in biochemical kinase assays (Huang et al., 2023).
• Exhibits >1000-fold selectivity for ATM versus ATR, DNA-PKcs, and mTOR kinases, minimizing off-target PIKK inhibition (APExBIO).
• Combining AZD0156 with DNA-damaging agents (e.g., topoisomerase inhibitors) enhances cancer cell death and suppresses tumor growth in preclinical models (Huang et al., 2023).
• ATM inhibition by AZD0156 induces metabolic adaptation in cancer cells, increasing macropinocytosis and amino acid uptake under nutrient-poor conditions (Huang et al., 2023).
• AZD0156 is orally bioavailable and achieves effective in vivo concentrations in murine models when administered at appropriate dosing regimens (APExBIO).

For further reading, see AZD0156: Potent ATM Kinase Inhibitor for Advanced Cancer ...—this article extends previous coverage by clarifying metabolic adaptation mechanisms and providing updated selectivity data.

Compare also AZD0156: Potent Selective ATM Kinase Inhibitor for Cancer...—the present article includes recent metabolic findings and workflow integration parameters not detailed previously.

Applications, Limits & Misconceptions

AZD0156 is valuable for research on:

• Dissecting DNA double-strand break repair and checkpoint control.
• Modeling synthetic lethality in ATM-deficient tumors.
• Studying metabolic adaptation and nutrient scavenging in cancer cells (Huang et al., 2023).
• Preclinical evaluation of combination therapies with genotoxic agents.

However, several boundaries must be recognized for rigorous interpretation.

Common Pitfalls or Misconceptions

• AZD0156 is not effective against non-PIKK kinases; selectivity must be confirmed per experiment.
• It does not restore function to ATM-deficient (null) cells but only inhibits residual ATM activity.
• Metabolic effects of ATM inhibition may be context-dependent and vary with p53/c-MYC status (Huang et al., 2023).
• AZD0156 is not water soluble and requires DMSO or ethanol for dissolution at specified concentrations (≥23.1 mg/mL in DMSO; ≥5.49 mg/mL in ethanol).
• Long-term storage of solutions is not recommended; use freshly prepared aliquots for consistency (APExBIO).

Workflow Integration & Parameters

AZD0156 is supplied as a solid (molecular weight 461.56 g/mol, C₂₆H₃₁N₅O₃) with >98% purity verified by HPLC and NMR (APExBIO). Dissolve in DMSO with gentle warming to achieve ≥23.1 mg/mL. For ethanol, solubility is ≥5.49 mg/mL. Store at -20°C. Use solutions immediately; avoid freeze-thaw cycles. For in vivo administration, oral gavage is supported in preclinical models. Shipping is on Blue Ice to preserve integrity. Researchers should consult QC documentation and titrate doses for specific assay endpoints.

For advanced experimental design and troubleshooting, see AZD0156: A Potent ATM Kinase Inhibitor for Advanced Cancer ...—the present article updates these workflows with recent selectivity and metabolic adaptation data.

Conclusion & Outlook

AZD0156, distributed by APExBIO, is a reference compound for selective ATM inhibition in cancer biology and DNA damage response research. It enables precise interrogation of DDR pathways, checkpoint control, and metabolic adaptation. Its high selectivity, oral bioavailability, and rigorous quality control make it a preferred reagent for preclinical and translational studies. Future research will refine combination strategies for exploiting ATM-dependent vulnerabilities and inform clinical translation. For detailed specifications, visit the AZD0156 product page.