AZD0156: Potent and Selective ATM Kinase Inhibitor for Cancer Research

Executive Summary: AZD0156 (SKU: B7822, CAS: 1821428-35-6) is a selective, orally bioavailable small-molecule inhibitor of ATM kinase, demonstrating sub-nanomolar inhibitory potency and >1000-fold selectivity versus other PIKK family enzymes (APExBIO). ATM is a serine/threonine kinase essential for genomic stability, DNA double-strand break repair, and checkpoint control (Kostaras et al., 2020). AZD0156 enhances antitumor efficacy in combination with DNA-damaging agents in preclinical models. The compound's defined chemical, physical, and storage parameters facilitate reproducibility and enable high-confidence experiment design. Its use in translational and mechanistic cancer research is supported by extensive peer-reviewed and product-supplied validation data.

Biological Rationale

ATM kinase (Ataxia Telangiectasia Mutated) is a serine/threonine protein kinase within the PIKK (phosphatidylinositol 3-kinase-related kinase) family. It is activated upon sensing DNA double-strand breaks (DSBs), orchestrating signaling cascades that regulate DNA repair, cell cycle checkpoints, and apoptosis (Kostaras et al., 2020). Dysfunctional ATM activity leads to impaired genomic stability and is implicated in cancer pathogenesis. Pharmacologic inhibition of ATM sensitizes tumor cells to DNA-damaging agents, creating a rationale for ATM inhibitors in cancer therapy research (see related; this article extends mechanistic detail and benchmarking evidence beyond previous reviews).

Mechanism of Action of AZD0156

AZD0156 is a competitive, small-molecule inhibitor that binds the catalytic domain of ATM kinase, preventing substrate phosphorylation and downstream signaling. The inhibitor displays sub-nanomolar IC₅₀ values against cellular ATM signaling and achieves >1000-fold selectivity versus other PIKK enzymes, including ATR and DNA-PKcs (APExBIO). Upon DNA damage, ATM autophosphorylation and subsequent activation of p53, CHK2, and other effectors are blocked by AZD0156, leading to impaired DNA repair and checkpoint response (see related; this article emphasizes selectivity data and practical workflow integration, not previously detailed).

Evidence & Benchmarks

• AZD0156 exhibits sub-nanomolar inhibition of ATM kinase in cellular assays (IC₅₀ < 1 nM, HCT116 cells, 2-hour incubation, 37°C) (APExBIO).
• Demonstrates >1000-fold selectivity against related kinases ATR, DNA-PKcs, and mTOR, as determined by kinase panel profiling (ATP-competitive assays, pH 7.4) (APExBIO).
• Enhances cytotoxicity of DNA double-strand break inducers (e.g., topoisomerase inhibitors) in xenograft cancer models, with a significant reduction in tumor volume compared to monotherapy (NOD/SCID mice, oral administration, 80 mg/kg daily, 21 days) (Kostaras et al., 2020).
• Displays favorable oral bioavailability and pharmacokinetic stability in rodent models (plasma t_1/2 > 5 hours, 20°C, vehicle: 0.5% methylcellulose) (APExBIO).
• Supplied at >98% purity verified by HPLC and NMR, with batch-specific QC data provided (APExBIO).
• Currently under early clinical investigation for advanced cancer, with preliminary safety and efficacy data being generated (Kostaras et al., 2020).

Applications, Limits & Misconceptions

AZD0156 is widely used in research targeting the DNA damage response, checkpoint control, and genomic stability in cancer biology. Its selectivity allows for precise dissection of ATM-dependent pathways and synergy with DNA-damaging therapies (see related; this article benchmarks selectivity and stability data not covered in the protocol-focused overview).

Common Pitfalls or Misconceptions

• AZD0156 is not effective against ATR, DNA-PKcs, or mTOR; its use is limited to ATM-dependent pathways (APExBIO).
• The compound is insoluble in water; improper solvent selection (e.g., aqueous buffers) leads to precipitation and loss of activity.
• Long-term storage of dissolved AZD0156 is not recommended; solutions should be prepared fresh and used promptly (APExBIO).
• Exclusively for research use; not approved for clinical or therapeutic application outside controlled studies.
• Some tumor models with defective downstream effectors (e.g., p53-null) may show attenuated response to ATM inhibition.

Workflow Integration & Parameters

AZD0156 (B7822) is provided by APExBIO as a solid, 461.56 g/mol, formula C₂₆H₃₁N₅O₃. For in vitro use, dissolve in DMSO (≥23.1 mg/mL with gentle warming); for in vivo use, formulate in ethanol (≥5.49 mg/mL) or suitable vehicles. Store solid at -20°C; ship with Blue Ice. Purity is batch-verified (>98%) by HPLC/NMR. For best results, use fresh solutions and avoid freeze-thaw cycles. Quality control data accompanies each shipment. The compound integrates smoothly into DNA damage response, cell viability, and signaling assays, and is compatible with co-treatment protocols involving DNA double-strand break inducers (see related; this article provides expanded stability and selectivity data for advanced assay design).

Conclusion & Outlook

AZD0156 stands as a leading tool for selective ATM kinase inhibition in cancer research, offering unmatched potency and specificity for dissecting DNA damage response pathways. The compound's robust pharmacological and physicochemical profile ensures experimental reproducibility across preclinical models. Ongoing clinical studies will clarify its translational potential in combination with DNA-damaging therapies. For mechanistic and translational research, AZD0156 from APExBIO provides a validated, high-quality solution for targeting genomic instability and checkpoint control in oncology.