AZD0156: Selective ATM Kinase Inhibitor for Cancer Research

Executive Summary: AZD0156 is a potent, orally bioavailable, and highly selective inhibitor of the ataxia telangiectasia mutated (ATM) kinase, a key regulator of the DNA damage response (DDR) in human cells (APExBIO). It demonstrates sub-nanomolar inhibition of ATM signaling, with >1000-fold selectivity over other PIKK family kinases (APExBIO QC data). Preclinical studies show that AZD0156 enhances the antitumor activity of agents that induce DNA double-strand breaks (Kostaras et al., 2020). Its molecular formula is C26H31N5O3, and recommended storage is at -20°C for optimal stability. Early clinical evaluation is ongoing to assess safety and efficacy in advanced cancer patients (APExBIO).

Biological Rationale

The ATM kinase is essential for cellular responses to DNA double-strand breaks. Upon DNA damage, ATM is activated and phosphorylates key substrates involved in DNA repair, cell cycle checkpoint control, and apoptosis. Dysfunction in the ATM pathway leads to genomic instability and increased cancer susceptibility. Selective inhibition of ATM is hypothesized to sensitize tumor cells to DNA-damaging agents by impeding repair and checkpoint pathways (APExBIO).

Mechanism of Action of AZD0156

AZD0156 is a small-molecule inhibitor designed to bind the active site of the ATM kinase, preventing ATP binding and subsequent kinase activity. It displays sub-nanomolar inhibitory potency against ATM in cell-based assays. The selectivity profile of AZD0156 exceeds 1000-fold over other PIKK family kinases, such as ATR and DNA-PKcs, ensuring minimal off-target effects (Kostaras et al., 2020). This high specificity allows for targeted investigation of ATM-dependent signaling in cancer and DNA repair studies.

Evidence & Benchmarks

• AZD0156 inhibits cellular ATM signaling at sub-nanomolar concentrations; IC50 values typically <1 nM in cell-based assays (APExBIO).
• Displays >1000-fold selectivity for ATM over related PIKK family kinases, such as ATR and DNA-PKcs (Kostaras et al., 2020).
• Enhances antitumor efficacy of DNA-damaging agents (e.g., radiation, topoisomerase II inhibitors) in preclinical cancer models when administered orally in combination (Kostaras et al., 2020).
• Presents as a solid with molecular weight 461.56 g/mol; soluble ≥23.1 mg/mL in DMSO at room temperature with gentle warming (APExBIO).
• Purity typically exceeds 98% by HPLC and NMR QC, as supplied by APExBIO (APExBIO).

Compared to prior discussions on precision ATM inhibition, this article provides a more granular, benchmark-focused breakdown of AZD0156's selectivity, workflow, and storage parameters.

Applications, Limits & Misconceptions

AZD0156 is widely used to study DNA damage response, checkpoint control, and synthetic lethality in cancer research. Its selectivity profile enables dissection of ATM-specific pathways without significant interference from related kinases. Key application areas include:

• Combination therapy studies with DNA-damaging agents in preclinical oncology models.
• Functional genomics to elucidate ATM-dependent DNA repair and checkpoint signaling.
• Probing synthetic lethal interactions in ATM-deficient or repair-compromised cancer cells (Transforming Cancer Research via ATM Inhibition; this article updates with more product-specific integration details).

For a comparative perspective on workflow optimization, see AZD0156: Selective ATM Kinase Inhibitor for Cancer Research. This dossier extends prior coverage by detailing solution preparation, storage, and QC parameters.

Common Pitfalls or Misconceptions

• AZD0156 is not effective in models reliant on ATR or DNA-PKcs signaling; selectivity for ATM is >1000-fold.
• It is insoluble in water; improper vehicle selection impairs assay consistency.
• Solutions of AZD0156 are not stable for long-term storage, even at -20°C; use promptly after preparation (APExBIO).
• AZD0156 is not indicated for diagnostic or therapeutic use in humans; currently for research use only.
• Non-target effects may arise at supraphysiological concentrations; dose controls are essential.

Workflow Integration & Parameters

AZD0156 is supplied as a solid by APExBIO (SKU: B7822) and is QC-verified for >98% purity. To prepare solutions, dissolve in DMSO to ≥23.1 mg/mL with gentle warming; ethanol can be used at ≥5.49 mg/mL for less concentrated stocks. Water is not suitable for dissolution. Store the powder at -20°C and avoid repeated freeze-thaw cycles. Use solutions immediately after preparation for optimal activity. Shipping is conducted on Blue Ice to maintain stability (APExBIO).

In cell-based assays, AZD0156 is typically used at concentrations ranging from 1 nM to 1 μM, depending on the experimental design. Combination protocols with DNA-damaging agents should include appropriate controls to distinguish additive from synergistic effects. Refer to Next Frontier in DNA Damage Response for advanced integration strategies; this dossier includes more explicit storage and solubility guidance.

Conclusion & Outlook

AZD0156 establishes a high benchmark for selective ATM kinase inhibition in cancer research. Its robust selectivity, chemical stability, and well-documented quality control make it the reagent of choice for dissecting ATM-dependent DNA damage responses. Ongoing clinical studies will clarify its therapeutic index and translational potential. For the latest protocols and ordering information, consult the official AZD0156 product page from APExBIO.