| Reference | 1. Thorax. 2017 Feb;72(2):182-185. doi: 10.1136/thoraxjnl-2016-209229. Epub 2016 Oct
24.
<br>
The cyclin-dependent kinase inhibitor AT7519 accelerates neutrophil apoptosis in
sepsis-related acute respiratory distress syndrome.
<br>
Dorward DA(1), Felton JM(1), Robb CT(1), Craven T(1), Kipari T(1), Walsh
TS(1)(2), Haslett C(1), Kefala K(2), Rossi AG(1), Lucas CD(1).
<br>
Author information: <br>
(1)The MRC Centre for Inflammation Research, Queen/’s Medical Research Institute,
University of Edinburgh, Edinburgh, UK.
(2)Department of Critical Care, Anaesthesia and Pain Medicine, Royal Infirmary of
Edinburgh, Edinburgh, UK.
<br>
Acute respiratory distress syndrome (ARDS) is a neutrophil-dominant disorder with
no effective pharmacological therapies. While the cyclin-dependent kinase
inhibitor AT7519 induces neutrophil apoptosis to promote inflammation resolution
in preclinical models of lung inflammation, its potential efficacy in ARDS has
not been examined. Untreated peripheral blood sepsis-related ARDS neutrophils
demonstrated prolonged survival after 20 hours in vitro culture. AT7519 was able
to override this phenotype to induce apoptosis in ARDS neutrophils with reduced
expression of the pro-survival protein Mcl-1. We demonstrate the first
pharmacological compound to induce neutrophil apoptosis in sepsis-related ARDS,
highlighting cyclin-dependent kinase inhibitors as potential novel therapeutic
agents.
<br>
2. Clin Cancer Res. 2015 Nov 15;21(22):5100-9. doi: 10.1158/1078-0432.CCR-15-0313.
Epub 2015 Jul 22.
<br>
Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent
Neuroblastoma.
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Dolman ME(1), Poon E(2), Ebus ME(3), den Hartog IJ(3), van Noesel CJ(4), Jamin
Y(5), Hallsworth A(2), Robinson SP(5), Petrie K(2), Sparidans RW(6), Kok RJ(7),
Versteeg R(3), Caron HN(8), Chesler L(2), Molenaar JJ(3).
<br>
Author information: <br>
(1)Department of Oncogenomics, Academic Medical Center, University of Amsterdam,
Amsterdam, the Netherlands. [email protected].
(2)Division of Clinical Studies, The Institute of Cancer Research, London,
England.
(3)Department of Oncogenomics, Academic Medical Center, University of Amsterdam,
Amsterdam, the Netherlands.
(4)Department of Pathology, Academic Medical Center, University of Amsterdam,
Amsterdam, the Netherlands.
(5)Division of Radiotherapy and Imaging, The Institute of Cancer Research,
London, England.
(6)Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht
University, Utrecht, the Netherlands.
(7)Division of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences
(UIPS), Faculty of Science, Utrecht University, Utrecht, the Netherlands.
(8)Department of Pediatric Oncology, Emma Kinderziekenhuis, Academic Medical
Center, University of Amsterdam, Amsterdam, the Netherlands.
<br>
PURPOSE: 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.<br>
EXPERIMENTAL DESIGN: 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.<br>
RESULTS: 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.<br>
CONCLUSIONS: This study strongly suggests that AT7519 is a promising drug for the
treatment of high-risk neuroblastoma patients with MYCN amplification.
<br>
3. J Pharm Biomed Anal. 2014 Jan;88:216-20. doi: 10.1016/j.jpba.2013.08.051. Epub
2013 Sep 12.
<br>
Liquid chromatography-tandem mass spectrometric assay for the cyclin-dependent
kinase inhibitor AT7519 in mouse plasma.
<br>
Dolman ME(1), den Hartog IJ, Molenaar JJ, Schellens JH, Beijnen JH, Sparidans RW.
<br>
Author information: <br>
(1)Amsterdam Medical Center, University of Amsterdam, Department of Oncogenomics,
Meibergdreef 15, PO Box 22700, 1105 AZ Amsterdam, The Netherlands.
<br>
A quantitative bioanalytical liquid chromatography-tandem mass spectrometric
(LC-MS/MS) assay for the cyclin-dependent kinase inhibitor AT7519 in mouse plasma
was developed and validated. Plasma samples were pre-treated using protein
precipitation with acetonitrile containing rucaparib as internal standard. After
dilution with water, the extract was directly injected into the reversed-phase LC
system. The eluate was transferred into the electrospray interface with positive
ionization and the analyte was detected in the selected reaction monitoring mode
of a triple quadrupole mass spectrometer. The assay was validated in a
5-10,000ng/ml calibration range using double logarithmic calibration, 5ng/ml was
the lower limit of quantification. Within day precisions (n=6) were 2.9-5.6%,
between day (3 days; n=18) precisions 3.2-7.2%. Accuracies were between 95.9 and
99.0% for the whole calibration range. The drug was stable under all relevant
analytical conditions. Finally, the assay was successfully used to determine
plasma pharmacokinetics after intraperitoneal administration of AT7519 in mice
with neuroblastoma xenografts.
<br>
4. Mol Cancer Ther. 2009 Feb;8(2):324-32. doi: 10.1158/1535-7163.MCT-08-0890. Epub
2009 Jan 27.
<br>
Biological characterization of AT7519, a small-molecule inhibitor of
cyclin-dependent kinases, in human tumor cell lines.
<br>
Squires MS(1), Feltell RE, Wallis NG, Lewis EJ, Smith DM, Cross DM, Lyons JF,
Thompson NT.
<br>
Author information: <br>
(1)Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge,
United Kingdom. [email protected]
<br>
Cyclin-dependent kinases (CDK), and their regulatory cyclin partners, play a
central role in eukaryotic cell growth, division, and death. This key role in
cell cycle progression, as well as their deregulation in several human cancers,
makes them attractive therapeutic targets in oncology. A series of CDK inhibitors
was developed using Astex/’s fragment-based medicinal chemistry approach, linked
to high-throughput X-ray crystallography. A compound from this series, designated
AT7519, is currently in early-phase clinical development. We describe here the
biological characterization of AT7519, a potent inhibitor of several CDK family
members. AT7519 showed potent antiproliferative activity (40-940 nmol/L) in a
panel of human tumor cell lines, and the mechanism of action was shown here to be
consistent with the inhibition of CDK1 and CDK2 in solid tumor cell lines. AT7519
caused cell cycle arrest followed by apoptosis in human tumor cells and inhibited
tumor growth in human tumor xenograft models. Tumor regression was observed
following twice daily dosing of AT7519 in the HCT116 and HT29 colon cancer
xenograft models. We show that these biological effects are linked to inhibition
of CDKs in vivo and that AT7519 induces tumor cell apoptosis in these xenograft
models. AT7519 has an attractive biological profile for development as a clinical
candidate, and the tolerability and efficacy in animal models compare favorably
with other CDK inhibitors in clinical development. Studies described here formed
the biological rationale for investigating the potential therapeutic benefit of
AT7519 in cancer patients.
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