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Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma.

Dolman, M Emmy M, Poon, Evon, Ebus, Marli E, den Hartog, Ilona J M, van Noesel, Carel J M, Jamin, Yann, Hallsworth, Albert, Robinson, Simon P, Petrie, Kevin, Sparidans, Rolf W, Kok, Robbert J, Versteeg, Rogier, Caron, Huib N, Chesler, Louis and Molenaar, Jan J (2015) Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research, 21 (22). pp. 5100-9. ISSN 1078-0432

Item Type: Article



MYCN-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.


Preclinical 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.


AT7519 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.


This study strongly suggests that AT7519 is a promising drug for the treatment of high-risk neuroblastoma patients with MYCN amplification.

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Depositing User: Kevin Petrie


Item ID: 12439
Identification Number:
ISSN: 1078-0432
Official URL:

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ORCID for Kevin Petrie: ORCID iD

Catalogue record

Date Deposited: 18 Aug 2020 18:49
Last Modified: 30 Sep 2020 10:48


Author: Kevin Petrie ORCID iD
Author: M Emmy M Dolman
Author: Evon Poon
Author: Marli E Ebus
Author: Ilona J M den Hartog
Author: Carel J M van Noesel
Author: Yann Jamin
Author: Albert Hallsworth
Author: Simon P Robinson
Author: Rolf W Sparidans
Author: Robbert J Kok
Author: Rogier Versteeg
Author: Huib N Caron
Author: Louis Chesler
Author: Jan J Molenaar

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine


Sciences > Biomedical Sciences
Sciences > Health Sciences

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