AZD0156: Potent Selective ATM Kinase Inhibitor for DNA Damage Response Research

Executive Summary: AZD0156 (B7822, CAS 1821428-35-6) is a small-molecule inhibitor developed for highly selective targeting of the ataxia telangiectasia mutated (ATM) kinase, a pivotal regulator of DNA double-strand break repair and checkpoint control in mammalian cells [APExBIO]. It exhibits sub-nanomolar cellular potency and over 1000-fold selectivity versus other PIKK family kinases, making it a gold-standard tool for dissecting ATM-dependent signaling. In preclinical models, AZD0156 boosts the efficacy of DNA-damaging agents and reveals unique metabolic vulnerabilities in cancer cells [Heliyon 2020]. The compound is supplied as a >98% pure solid, is orally bioavailable, and is widely used in advanced cancer biology workflows to probe DNA repair and checkpoint modulation. Early clinical studies indicate its safety profile and translational potential in combination therapy [APExBIO].

Biological Rationale

The ATM kinase is a serine/threonine protein kinase belonging to the phosphatidylinositol 3-kinase-related kinase (PIKK) family. ATM is activated by DNA double-strand breaks (DSBs) and orchestrates cellular responses to genomic damage, including checkpoint activation, DNA repair, and apoptosis or senescence induction [Heliyon 2020]. Defects in ATM function underlie the disorder ataxia telangiectasia, which is associated with cancer predisposition and genomic instability. Elevated ATM activity has been observed in several tumors, including high-grade serous ovarian cancer (HGSOC), where it is associated with poor prognosis. Targeting ATM in HR-proficient tumors addresses the unmet need for new cancer therapies beyond PARP inhibitors, which are only effective in HR-deficient backgrounds. ATM inhibition also modulates metabolic pathways, suggesting broader implications for cellular adaptation to stress.

Mechanism of Action of AZD0156

AZD0156 is a reversible, ATP-competitive inhibitor of ATM kinase. It blocks ATM autophosphorylation and subsequent phosphorylation of downstream substrates such as Chk2 and H2AX in response to DNA DSBs. This inhibition disrupts initiation of the DNA damage checkpoint, impairs homologous recombination repair, and sensitizes cells to agents that induce DSBs (e.g., irradiation, topoisomerase inhibitors, PARP inhibitors) [Heliyon 2020]. AZD0156 displays over 1000-fold greater selectivity for ATM versus related PIKK kinases (ATR, DNA-PKcs, mTOR) in biochemical and cellular assays [APExBIO]. The compound's molecular weight is 461.56 g/mol, and its chemical formula is C26H31N5O3. It is orally bioavailable and achieves sufficient in vivo exposure to inhibit ATM signaling in tumor xenograft models. The selective inhibition of ATM by AZD0156 enables precise dissection of ATM-dependent processes such as checkpoint regulation, DNA repair, and metabolic adaptation in cancer cells.

Evidence & Benchmarks

• AZD0156 inhibits ATM kinase with sub-nanomolar cellular potency, showing >1000-fold selectivity over ATR and DNA-PKcs (APExBIO, product page).
• In HGSOC models, ATM inhibition with AZD0156 synergizes with metabolic drugs (e.g., fenofibrate), inducing senescence and reducing cancer cell viability (Heliyon 2020).
• Combined ATM inhibition and DNA-damaging agents (e.g., PARP inhibitors, irradiation) enhance antitumor efficacy in preclinical models (Heliyon 2020).
• AZD0156 is >98% pure by HPLC and NMR and is stable when stored at -20°C (APExBIO, product page).
• Phase I clinical trials have commenced to assess AZD0156 safety and efficacy in advanced cancers (Heliyon 2020).

For a comprehensive mechanistic analysis of AZD0156's checkpoint modulation and metabolic effects, see AZD0156: Unlocking ATM Kinase Inhibition for Genomic Stability, which provides complementary discussion but does not address the latest clinical integration detailed here.

For a deep-dive into metabolic pathway adaptations revealed by ATM inhibition, AZD0156: Precision ATM Inhibition to Unravel Metabolic and DNA Repair Pathways offers mechanistic insights, while this article emphasizes translational benchmarks and workflow parameters.

Applications, Limits & Misconceptions

AZD0156 is used extensively in preclinical and translational research focused on DNA damage response, cancer therapy, and genomic stability regulation. Its primary applications include:

• Studying ATM-dependent DNA repair and checkpoint signaling in HR-proficient and deficient cancer models.
• Evaluating synergistic effects with DNA-damaging agents (e.g., PARP inhibitors, chemotherapies).
• Investigating links between DNA repair and metabolic adaptation in cancer cells.
• Developing combination therapies for tumors resistant to standard-of-care regimens.

Common Pitfalls or Misconceptions

• AZD0156 is not effective as monotherapy in most solid tumors; combinatorial regimens are typically required (Heliyon 2020).
• It is highly selective for ATM but does not inhibit other PIKK kinases (e.g., ATR, DNA-PKcs) at relevant concentrations (APExBIO).
• AZD0156 is not water soluble; DMSO or ethanol are required for solution preparation (APExBIO).
• Long-term storage of AZD0156 solutions is not recommended; fresh solutions should be used for experiments.
• Clinical efficacy and safety are under investigation; current use is limited to research applications.

For additional discussion of DNA repair and metabolic vulnerabilities, see AZD0156: A Selective ATM Kinase Inhibitor Redefining Cancer Therapy, which provides further background but does not cover the latest purity and workflow integration details described here.

Workflow Integration & Parameters

AZD0156 is supplied by APExBIO (SKU: B7822) as a solid, typically >98% pure by HPLC and NMR. The recommended storage temperature is -20°C. For use, dissolve in DMSO at ≥23.1 mg/mL with gentle warming, or in ethanol at ≥5.49 mg/mL. The compound is insoluble in water. Prepare fresh solutions for each experiment to ensure stability and potency. Shipping is under Blue Ice conditions for small molecules. AZD0156 is compatible with cellular, molecular, and in vivo models for DNA damage response and cancer therapy research. Quality control data and certificate of analysis are provided with each lot. For detailed handling and application guidance, refer to the AZD0156 product page.

Conclusion & Outlook

AZD0156 is a next-generation, potent, and selective ATM kinase inhibitor enabling high-precision research into DNA double-strand break repair, checkpoint modulation, and metabolic vulnerabilities in cancer. Its use in combination regimens is supported by preclinical and emerging clinical data, positioning it as a valuable tool in translational oncology research. As further clinical results become available, AZD0156 is expected to refine therapeutic strategies targeting the DNA damage response and genomic stability regulation. For up-to-date product specifications and ordering, visit the APExBIO AZD0156 page.