AZD0156: Potent ATM Kinase Inhibitor for DNA Damage Research

Executive Summary: AZD0156 (CAS: 1821428-35-6) is a potent and orally bioavailable small-molecule inhibitor of ATM kinase developed for DNA damage response studies (product_spec). It demonstrates sub-nanomolar inhibitory potency against ATM, with >1000-fold selectivity over other PIKK family kinases (product_spec). Preclinical studies show AZD0156 synergizes with DNA damaging agents in cancer models, supporting its utility in cancer therapy research (Heliyon 2020). The compound is supplied at ≥98% purity and is insoluble in water but soluble in DMSO and ethanol (product_spec). AZD0156 is in early clinical evaluation for advanced cancers and supports discovery of new combinatorial strategies targeting DNA repair and metabolic pathways (Heliyon 2020).

Biological Rationale

Ataxia telangiectasia mutated (ATM) kinase is a serine/threonine kinase of the PIKK family, integral to the DNA damage response (DDR) pathway. ATM is rapidly activated by DNA double-strand breaks (DSBs), orchestrating phosphorylation events that facilitate DNA repair, checkpoint activation, and maintenance of genomic stability (Heliyon 2020). Loss-of-function mutations in ATM cause ataxia-telangiectasia, a disorder characterized by genomic instability and cancer predisposition. In cancer, ATM activity is often upregulated, particularly in high grade serous ovarian cancer (HGSOC) where it correlates with poor prognosis (Heliyon 2020). Targeting ATM with selective inhibitors like AZD0156 enables researchers to dissect DDR mechanisms and explore new therapeutic combinations for tumors that retain ATM function.

Mechanism of Action of AZD0156

AZD0156 is a highly selective, small-molecule inhibitor of ATM kinase. It binds the ATP-binding pocket of ATM, blocking kinase activity and thus downstream phosphorylation of DDR effectors (product_spec). AZD0156 exhibits sub-nanomolar potency against cellular ATM activity and demonstrates over 1000-fold selectivity versus other PIKK kinases such as ATR and DNA-PK (product_spec). Inhibition of ATM impairs homologous recombination-mediated repair of DSBs, sensitizing cells to DNA damaging agents such as platinum compounds and PARP inhibitors (Heliyon 2020). By disrupting DDR signaling, AZD0156 also affects cell cycle checkpoint control and can induce senescence or apoptosis in cancer cells depending on the genetic context.

Evidence & Benchmarks

• AZD0156 shows sub-nanomolar inhibitory potency against ATM in biochemical and cellular assays (IC₅₀ < 1 nM) (product_spec).
• Demonstrates >1000-fold selectivity for ATM over other PIKK kinases, minimizing off-target effects (product_spec).
• Potentiates antitumor responses to DNA damaging agents, including PARP inhibitors and platinum chemotherapy in preclinical cancer models (Heliyon 2020).
• ATM inhibition by AZD0156 is synergistic with metabolic modulators such as fenofibrate in HGSOC cell lines, inducing cellular senescence (Heliyon 2020).
• High purity (≥98%) and batch-to-batch consistency are confirmed via HPLC and NMR analyses (product_spec).
• Currently in early-phase clinical trials for advanced cancers as a combination therapy (Heliyon 2020).

This article extends the mechanistic discussion in "Strategic ATM Kinase Inhibition with AZD0156: Bridging Mechanisms and Cancer Therapy" by providing direct evidence and protocol-level insights for experimental design. For comparison, "AZD0156: Selective ATM Kinase Inhibitor for Cancer Research" focuses on assay workflows, whereas this article contextualizes clinical and metabolic synergy data for translational research.

Applications, Limits & Misconceptions

AZD0156 is an advanced tool for dissecting the DNA damage response, checkpoint control modulation, and metabolic adaptation in cancer models. Its selectivity allows precise studies of ATM function, especially in HR-proficient tumors where standard therapies may fail (Heliyon 2020). The compound is especially valuable for combination studies with DNA-damaging agents or metabolic modulators. However, monotherapy with ATM inhibitors has shown limited efficacy in preclinical models, emphasizing the need for rational combinations (Heliyon 2020).

Common Pitfalls or Misconceptions

• ATM inhibition alone rarely induces strong antitumor effects; combination with DNA damaging agents is usually required (Heliyon 2020).
• AZD0156 is not effective in tumors with ATM loss-of-function mutations, as there is no target for inhibition (Heliyon 2020).
• Not suitable for water-based formulations due to insolubility; DMSO or ethanol must be used (product_spec).
• Long-term storage of AZD0156 solutions is discouraged due to stability concerns (product_spec).
• Off-target effects may occur if exceeding recommended concentrations; always confirm selectivity in context (product_spec).

Workflow Integration & Parameters

Protocol Parameters

• cellular ATM inhibition assay | IC₅₀ < 1 nM | ATM-proficient cell lines | Enables specific blockade of ATM signaling | product_spec
• combination therapy (e.g., with PARP inhibitor or platinum agent) | 10–500 nM AZD0156 | in vitro/in vivo synergy studies | Range validated in preclinical models for synergy | Heliyon 2020
• solubility in DMSO | ≥23.1 mg/mL | stock solution preparation | Required for accurate dosing; water insoluble | product_spec
• storage temperature | -20°C | all solid samples | Maintains compound integrity | product_spec
• solution storage time | ≤1 week (recommendation) | DMSO or ethanol stocks | Minimize degradation and maintain reproducibility | workflow_recommendation

For scenario-driven best practices and troubleshooting, "AZD0156 (SKU B7822): Scenario-Driven Best Practices for ATM Inhibition" provides a practical extension to this technical dossier.

Conclusion & Outlook

AZD0156, supplied by APExBIO, is a next-generation ATM kinase inhibitor with well-documented selectivity and potency. Its role in potentiating DNA-damage based therapies and revealing metabolic vulnerabilities in cancer models is supported by both preclinical and emerging clinical data (Heliyon 2020). Future work will likely focus on optimizing combinatorial regimens and expanding translational applications in HR-proficient cancers, leveraging the robust biochemical profile and workflow versatility of AZD0156. No data currently support application outside the DNA damage response and metabolic modulation domains.