AZD0156: Potent Selective ATM Kinase Inhibitor for Cancer Research

Executive Summary: AZD0156 (CAS 1821428-35-6) is a potent, orally bioavailable, and highly selective inhibitor of the ATM kinase, a pivotal enzyme in the DNA damage response (DDR) pathway (APExBIO). It exhibits sub-nanomolar potency and over 1000-fold selectivity for ATM over other PIKK family kinases, with purity typically exceeding 98% (HPLC/NMR; product QC). AZD0156 enhances the antitumor activity of DNA-damaging agents in preclinical models. Its chemical stability and solubility profiles make it ideal for rigorous research applications, and APExBIO supplies it with comprehensive quality control. The compound is central to studies aiming to dissect checkpoint control, genomic stability, and therapeutic resistance in cancer (Kostaras et al., 2020).

Biological Rationale

ATM (ataxia telangiectasia mutated) is a serine/threonine kinase belonging to the phosphatidylinositol 3-kinase-related kinase (PIKK) family. It orchestrates the cellular response to DNA double-strand breaks (DSBs) by activating DNA repair, cell cycle checkpoints, and apoptosis pathways (Kostaras et al., 2020). ATM activation is essential for genomic stability. Defective ATM signaling leads to impaired DNA repair and is implicated in tumorigenesis and cancer therapy resistance. Inhibiting ATM sensitizes cancer cells to DNA-damaging agents and is a promising strategy for enhancing the efficacy of chemotherapeutics and radiotherapy. AZD0156 provides researchers a tool to selectively interrogate ATM-dependent processes and to dissect their roles in cancer progression and therapeutic response (related article: AZD0156: Selective ATM Kinase Inhibitor for Cancer Research).

Mechanism of Action of AZD0156

AZD0156 is a small-molecule inhibitor that binds selectively to the catalytic site of ATM kinase, inhibiting its serine/threonine phosphorylation activity. This blockade prevents ATM-mediated phosphorylation of key DDR substrates, including p53, CHK2, and H2AX, which are required for efficient checkpoint control and DNA repair (APExBIO). The compound exhibits sub-nanomolar cellular potency (IC₅₀ < 1 nM in biochemical assays) and demonstrates >1000-fold selectivity over related kinases such as ATR, DNA-PK, and mTOR. In cell-based assays, AZD0156 suppresses ATM signaling in response to ionizing radiation or chemotherapeutic-induced DNA damage, resulting in increased DNA damage accumulation, checkpoint abrogation, and cell death in susceptible tumor models (Kostaras et al., 2020).

Evidence & Benchmarks

• AZD0156 inhibits ATM kinase activity with sub-nanomolar potency (IC₅₀ <1 nM, in vitro biochemical assay) (APExBIO).
• Displays >1,000-fold selectivity for ATM over other PIKK family members (ATR, DNA-PK, mTOR) in kinase profiling assays (APExBIO).
• Suppresses phosphorylation of ATM substrates (e.g., p53 Ser15, H2AX Ser139) following DNA double-strand break induction (Kostaras et al., 2020).
• Enhances antitumor efficacy of DNA-damaging agents (e.g., topoisomerase inhibitors, ionizing radiation) in preclinical xenograft models (Kostaras et al., 2020).
• AZD0156 is orally bioavailable, with a molecular weight of 461.56 g/mol and solubility of ≥23.1 mg/mL in DMSO at room temperature (APExBIO).
• Stability requires storage at -20°C; solutions should be used promptly for optimal activity (APExBIO).
• Early clinical data demonstrate manageable safety and pharmacodynamic modulation of ATM signaling in advanced cancer patients (Kostaras et al., 2020).

For a broader discussion of AZD0156's role in checkpoint control and metabolic adaptation, see AZD0156 and the New Frontier in ATM Kinase Inhibition, which expands on translational applications not detailed here.

Applications, Limits & Misconceptions

AZD0156 is widely used in academic and industrial research to:

• Dissect DNA double-strand break (DSB) repair pathways and checkpoint control in cancer cells.
• Investigate synthetic lethality with PARP inhibitors and other DDR-targeted agents.
• Elucidate mechanisms of therapeutic resistance and tumor adaptation.
• Model metabolic vulnerabilities arising from ATM inhibition (see also: AZD0156: Precision ATM Inhibition Reshaping Cancer Metabo... for more on metabolic effects).
• Support translational workflows for oncology drug development.

Common Pitfalls or Misconceptions

• AZD0156 is not a pan-PIKK inhibitor and does not significantly inhibit ATR, DNA-PK, or mTOR at research-relevant concentrations.
• It is ineffective in ATM-null cell lines; activity depends on functional ATM expression.
• AZD0156 does not substitute for direct DNA-damaging agents; it is a sensitizer, not a cytotoxin.
• Long-term solution storage (>24 hours) at room temperature leads to compound degradation and reduced potency.
• In vivo efficacy and safety in humans remain under clinical investigation; results from animal models may not fully predict patient response.

For step-by-step protocol guidance and troubleshooting strategies, AZD0156: Advanced ATM Kinase Inhibitor for Cancer Research provides detailed workflow instructions, which this article updates with current selectivity and storage data.

Workflow Integration & Parameters

• Solubility: Dissolve AZD0156 at concentrations ≥23.1 mg/mL in DMSO with gentle warming. Moderately soluble in ethanol (≥5.49 mg/mL). Insoluble in water (APExBIO).
• Storage: Store as a solid at -20°C. Prepare solutions fresh; avoid long-term storage.
• Purity: Supplied at ≥98% (HPLC and NMR QC data provided by APExBIO).
• Shipping: Dispatched with Blue Ice to maintain stability.
• Quality Control: Each batch accompanied by HPLC/NMR purity data and batch traceability.
• Usage: Typical working concentrations in cell-based assays range from 0.01 to 1 µM, depending on model and endpoint. For in vivo studies, dosing should follow published pharmacokinetics and safety data.

For practical applications in checkpoint modulation and metabolic adaptation studies, review AZD0156: Selective ATM Kinase Inhibitor for Cancer Research, which this dossier clarifies by addressing new evidence on selectivity and workflow integration.

Conclusion & Outlook

AZD0156 represents a best-in-class tool for probing ATM-dependent DNA damage response mechanisms. Its high selectivity, oral bioavailability, and robust quality control make it a standard for cancer research workflows. Ongoing clinical studies will clarify its translational potential, but current evidence supports AZD0156 as a critical reagent for dissecting checkpoint control, genomic stability regulation, and therapeutic vulnerabilities in oncology. For further details or to order, see the AZD0156 product page at APExBIO.