AZD0156: Highly Selective ATM Kinase Inhibitor for Cancer Research

Executive Summary: AZD0156 (CAS: 1821428-35-6) is a small-molecule inhibitor with sub-nanomolar potency and >1000-fold selectivity for ATM kinase over other PIKK family members, enabling precise inhibition of DNA double-strand break repair pathways (APExBIO). ATM kinase is central to homologous recombination-mediated DNA repair and checkpoint regulation, making it a critical target in cancer models with elevated ATM activity (Chen et al., 2020). Preclinical data demonstrate that AZD0156 synergizes with agents such as PARP inhibitors and irradiation, but not as effective monotherapy. The compound is orally bioavailable, stable at -20°C, and widely used in translational workflows to probe genomic stability and metabolic adaptation (AZD7687.com). AZD0156 is currently supplied by APExBIO with >98% purity for research use only.

Biological Rationale

ATM (Ataxia Telangiectasia Mutated) kinase is a serine/threonine protein kinase in the phosphatidylinositol 3-kinase-related kinase (PIKK) family. It detects DNA double-strand breaks (DSBs) and orchestrates the DNA damage response (DDR) by phosphorylating downstream effectors involved in repair, checkpoint control, and apoptosis (Chen et al., 2020). Germline ATM mutations cause Ataxia Telangiectasia, leading to genomic instability, cancer predisposition, and metabolic dysfunction. In tumors such as high-grade serous ovarian cancer (HGSOC), ATM is often wildtype and overexpressed, correlating with poor prognosis. ATM activity is essential for homologous recombination-mediated DSB repair and for maintaining genomic integrity. Targeting ATM is therefore a rational strategy where DNA repair pathways are upregulated and resistance to PARP inhibitors is common.

Mechanism of Action of AZD0156

AZD0156 is a potent, highly selective, and orally bioavailable inhibitor of ATM kinase. The compound binds to the active site of ATM, blocking its phosphorylation activity on downstream targets (e.g., p53, CHK2, H2AX). Inhibition occurs at sub-nanomolar concentrations, with >1000-fold selectivity relative to other PIKK kinases such as ATR, DNA-PKcs, and mTOR (APExBIO). This specificity enables researchers to dissect ATM-dependent functions in DDR without confounding off-target effects. AZD0156 disrupts DNA repair checkpoint signaling, leading to persistent DSBs, impaired cell cycle arrest, and increased apoptosis in ATM-dependent cancer cells. It also reveals metabolic vulnerabilities, as ATM inhibition modulates pathways such as fatty acid oxidation and glycolysis, especially when combined with metabolic drugs (Chen et al., 2020).

Evidence & Benchmarks

• AZD0156 achieves sub-nanomolar inhibition of ATM kinase in cellular assays (IC₅₀ < 1 nM at 37°C, pH 7.4) (APExBIO).
• Exhibits >1000-fold selectivity over other PIKK family kinases, confirmed by kinase profiling (APExBIO).
• Oral AZD0156 enhances antitumor efficacy when combined with DNA-damaging agents in preclinical cancer models (e.g., PARP inhibitors, irradiation) (Chen et al., 2020).
• ATM inhibition via AZD0156 induces cellular senescence and metabolic reprogramming, especially in combination with PPARα agonists such as fenofibrate (Chen et al., 2020).
• Clinical trials are underway to assess AZD0156 safety and preliminary efficacy in patients with advanced solid tumors (see clinicaltrials.gov).

This article extends guidance from 'AZD0156: Potent ATM Kinase Inhibitor for Precision Cancer...' by focusing on experimental benchmarks and clinical translation, whereas the referenced guide emphasizes applied workflows and troubleshooting strategies. For a mechanistic overview of metabolic adaptation, see 'AZD0156: Precision ATM Inhibition Reshaping Cancer Metabo...', which this article updates with current peer-reviewed clinical benchmarks.

Applications, Limits & Misconceptions

AZD0156 is widely used in research on DNA damage response pathways, checkpoint control, and metabolic adaptation in cancer biology. It enables the study of ATM-dependent DSB repair, synthetic lethality with PARP inhibitors, and the identification of metabolic vulnerabilities. However, its efficacy as a monotherapy is limited; combinatorial approaches with DNA-damaging agents or metabolic modulators yield stronger antitumor responses (Chen et al., 2020). AZD0156 is not effective in tumors with ATM loss-of-function mutations or complete deficiency, as its action requires functional ATM protein.

Common Pitfalls or Misconceptions

• AZD0156 is not a broad-spectrum PIKK inhibitor: Its >1000-fold selectivity restricts activity primarily to ATM kinase (APExBIO).
• Limited efficacy as monotherapy: AZD0156 alone does not produce significant antitumor effects in most preclinical models; combination with DNA-damaging agents is critical (Chen et al., 2020).
• Not suitable for ATM-null or mutant models: The compound requires wildtype, functional ATM protein for activity.
• Poor aqueous solubility: AZD0156 is insoluble in water; use DMSO (≥23.1 mg/mL) or ethanol (≥5.49 mg/mL) with gentle warming for stock solutions.
• Not for clinical or diagnostic use: For research use only; clinical application requires regulatory approval.

Workflow Integration & Parameters

The B7822 kit from APExBIO supplies AZD0156 as a solid with molecular weight 461.56 g/mol (C₂₆H₃₁N₅O₃), >98% purity (HPLC/NMR). For in vitro studies, dissolve in DMSO to ≥23.1 mg/mL with gentle warming; store aliquots at -20°C and use promptly, as long-term solution storage is discouraged. For in vivo studies, oral administration is standard; refer to published protocols for dosing regimens. Quality control includes HPLC and NMR purity data. Shipping uses Blue Ice for stability. AZD0156 is widely integrated in workflows studying DNA double-strand break repair, checkpoint modulation, and metabolic adaptation. For advanced experimental strategies and troubleshooting, researchers may consult 'Beyond DNA Repair: Strategic Exploitation of ATM Inhibiti...', which this article clarifies by providing updated benchmark data and usage caveats.

Conclusion & Outlook

AZD0156 is a benchmark ATM kinase inhibitor, enabling highly specific interrogation of DNA damage response, checkpoint control, and metabolic vulnerabilities in cancer models. Its selectivity and potency facilitate discovery of synthetic lethal interactions and inform combinatorial therapy strategies. Ongoing clinical trials and recent mechanistic studies support continued development of AZD0156 for translational research. For detailed protocols, purity documentation, and ordering information, refer to the official APExBIO AZD0156 product page.