ArticleMolecular cancer therapeutics2022
A New Class of Selective ATM Inhibitors as Combination Partners of DNA Double-Strand Break Inducing Cancer Therapies.
Article in Molecular cancer therapeutics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 1 of them a synthesis that pooled it.
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Who cites it
34 citing papers in PubMed, 1 synthesis or guideline pooled it, 46 citations in OpenAlex.
- Targeting DNA damage response to enhance cancer immunotherapy efficacy: molecular mechanisms and clinical advances.Medical oncology (Northwood, London, England) · 2025Pooled it
- The next generation of antibody-drug conjugates.Nature medicine · 2026Review
- Molecular Characterization of PARP Inhibitor Response Reveals Co-Targeting Strategies in Advanced Prostate Cancer.Cancers · 2026Article
- Drugging non-canonical kinases in cancer therapeutics: Molecular targets, underlying mechanisms and small-molecule inhibitors.Acta pharmaceutica Sinica. B · 2026Review
- Characterizing Response to PARP Inhibitor Treatment Combinations in Advanced Prostate Cancer.Biomedicines · 2026Article
- Human iPSC-derived and conventional cancer models in precision oncology: advancing patient-specific therapies from bench to bedside.Journal of experimental & clinical cancer research : CR · 2026Review
- Radiogenomics and the DNA damage response: opportunities for biomarker-guided radiosensitization in pancreatic cancer.Frontiers in oncology · 2026Review
- Promising Targets and Drugs for Improving Head and Neck Cancer Response to Radiotherapy.Current pharmaceutical design · 2026Review
- Next Generation DNA Damage Response Inhibitors: Harnessing Nanocarriers and Tumor Microenvironment for Precision Cancer Therapy.Oncology research · 2026Review
- A First-in-Human Study of ATM Inhibitor Lartesertib as Monotherapy in Patients with Advanced Solid Tumors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- The novel brain penetrant ataxia-telangiectasia mutated inhibitor WSD0628 provides robust radiosensitization of brain tumor patient-derived xenografts.Neuro-oncology · 2025Article
- Cancer Vulnerabilities Through Targeting the ATR/Chk1 and ATM/Chk2 Axes in the Context of DNA Damage.Cells · 2025Review
- The Development of ATM Inhibitors in Cancer Therapy.Targeted oncology · 2025Review
- Modeling the Acute Mucosal Toxicity of Fractionated Radiotherapy Combined with the ATM Inhibitor WSD0628.Molecular cancer therapeutics · 2025Article
- ATM in immunobiology: From lymphocyte development to cancer immunotherapy.Translational oncology · 2025Review
- Targeting the DNA damage response in cancer.MedComm · 2024Review
- Consensus, debate, and prospective on pancreatic cancer treatments.Journal of hematology & oncology · 2024Review
- PROTAC-mediated conditional degradation of the WRN helicase as a potential strategy for selective killing of cancer cells with microsatellite instability.Scientific reports · 2024Article
- Tumor biomarkers for diagnosis, prognosis and targeted therapy.Signal transduction and targeted therapy · 2024Review
- Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization.Science translational medicine · 2024Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Radiotherapy and chemical DNA-damaging agents are among the most widely used classes of cancer therapeutics today. Double-strand breaks (DSB) induced by many of these treatments are lethal to cancer cells if left unrepaired. Ataxia telangiectasia-mutated (ATM) kinase plays a key role in the DNA damage response by driving DSB repair and cell-cycle checkpoints to protect cancer cells. Inhibitors of ATM catalytic activity have been shown to suppress DSB DNA repair, block checkpoint controls and enhance the therapeutic effect of radiotherapy and other DSB-inducing modalities. Here, we describe the pharmacological activities of two highly potent and selective ATM inhibitors from a new chemical class, M3541 and M4076. In biochemical assays, they inhibited ATM kinase activity with a sub-nanomolar potency and showed remarkable selectivity against other protein kinases. In cancer cells, the ATM inhibitors suppressed DSB repair, clonogenic cancer cell growth, and potentiated antitumor activity of ionizing radiation in cancer cell lines. Oral administration of M3541 and M4076 to immunodeficient mice bearing human tumor xenografts with a clinically relevant radiotherapy regimen strongly enhanced the antitumor activity, leading to complete tumor regressions. The efficacy correlated with the inhibition of ATM activity and modulation of its downstream targets in the xenograft tissues. In vitro and in vivo experiments demonstrated strong combination potential with PARP and topoisomerase I inhibitors. M4076 is currently under clinical investigation.
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