ArticleClinical cancer research : an official journal of the American Association for Cancer Research2015
Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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36 citing papers in PubMed, 67 citations in OpenAlex.
- Targeting MYC-Driven Cancers: From Oncogenic Addiction to Therapeutic Vulnerability.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2026Review
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- CDK2 inhibition promotes neuronal differentiation in neuroblastoma.Scientific reports · 2026Article
- In silico-driven identification of potent CDK9 inhibitors through bioisosteric replacement and multi-stage virtual screening.Scientific reports · 2025Article
- The Duality of Cdk5: A Master Regulator in Neurodevelopment and a Hijacked Oncogene in Cancer.Cells · 2025Review
- Phosphoproteomic and Acetylomic Characterization of Colorectal Cancer Cells Treated with Kinase Inhibitors.ACS pharmacology & translational science · 2025Article
- CDK inhibitors promote neuroblastoma cell differentiation and increase sensitivity to retinoic acid-a promising combination strategy for therapeutic intervention.Cell death discovery · 2025Article
- Novel Small Molecule Inhibitors of Cyclin-dependent Kinases as Anticancer Agents.Current medicinal chemistry · 2025Review
- 3-chymotrypsin-like protease in SARS-CoV-2.Bioscience reports · 2024Review
- Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario.Pharmaceutics · 2023Review
- CDK9 inhibitors in cancer research.RSC medicinal chemistry · 2022Review
- TP53 and TP53-associated genes are correlated with the prognosis of paediatric neuroblastoma.BMC genomic data · 2022Article
- High-Throughput Screening Identifies Idasanutlin as a Resensitizing Drug for Venetoclax-Resistant Neuroblastoma Cells.Molecular cancer therapeutics · 2021Article
- Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma-backbone or add-on in immune-oncology?Cancer metastasis reviews · 2021Review
- Targeting oncoproteins with a positive selection assay for protein degraders.Science advances · 2021Article
- CDK inhibitors in cancer therapy, an overview of recent development.American journal of cancer research · 2021Review
- Integrated Genomic Profiling and Drug Screening of Patient-Derived Cultures Identifies Individualized Copy Number-Dependent Susceptibilities Involving PI3K Pathway and 17q Genes in Neuroblastoma.Frontiers in oncology · 2021Article
- Review
- Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma.The Journal of clinical investigation · 2020Article
- NMR as a "Gold Standard" Method in Drug Design and Discovery.Molecules (Basel, Switzerland) · 2020Review
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Authors and funding
15 authors at 1 institution in 1 country.
Funding
Abstract
purposeMYCN-dependent neuroblastomas have low cure rates with current multimodal treatment regimens and novel therapeutic drugs are therefore urgently needed. In previous preclinical studies, we have shown that targeted inhibition of cyclin-dependent kinase 2 (CDK2) resulted in specific killing of MYCN-amplified neuroblastoma cells. This study describes the in vivo preclinical evaluation of the CDK inhibitor AT7519. EXPERIMENTAL
designPreclinical drug testing was performed using a panel of MYCN-amplified and MYCN single copy neuroblastoma cell lines and different MYCN-dependent mouse models of neuroblastoma.
resultsAT7519 killed MYCN-amplified neuroblastoma cell lines more potently than MYCN single copy cell lines with a median LC50 value of 1.7 compared to 8.1 μmol/L (P = 0.0053) and a significantly stronger induction of apoptosis. Preclinical studies in female NMRI homozygous (nu/nu) mice with neuroblastoma patient-derived MYCN-amplified AMC711T xenografts revealed dose-dependent growth inhibition, which correlated with intratumoral AT7519 levels. CDK2 target inhibition by AT7519 was confirmed by significant reductions in levels of phosphorylated retinoblastoma (p-Rb) and nucleophosmin (p-NPM). AT7519 treatment of Th-MYCN transgenic mice resulted in improved survival and clinically significant tumor regression (average tumor size reduction of 86% at day 7 after treatment initiation). The improved efficacy of AT7519 observed in Th-MYCN mice correlated with higher tumor exposure to the drug.
conclusionsThis study strongly suggests that AT7519 is a promising drug for the treatment of high-risk neuroblastoma patients with MYCN amplification.
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