Reference : Cooperative effects of Janus and Aurora kinase inhibition by CEP701 in cells expressi...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/10993/15766
Cooperative effects of Janus and Aurora kinase inhibition by CEP701 in cells expressing Jak2V617F
English
Gäbler, Karoline mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Rolvering, Catherine mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Kaczor, Jakub [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Eulenfeld, R. [Institute of Biology, Department of Systems Biology, Otto-von-Guericke-University, Magdeburg, Germany]
Méndez, S. A. [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Berchem, G. [Department of Oncology, Laboratory of Experimental Hemato-Oncology, CRP Santé, Luxembourg, Luxembourg]
Palissot, V. [Department of Oncology, Laboratory of Experimental Hemato-Oncology, CRP Santé, Luxembourg, Luxembourg]
Behrmann, Iris mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Haan, Claude mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
2013
Journal of Cellular & Molecular Medicine
Blackwell Publishing
17
2
265-276
Yes (verified by ORBilu)
International
1582-1838
[en] Aurora kinases; CEP701; Jak2V617F; Janus kinases; Kinase inhibitors; MPN
[en] The Janus kinase 2 mutant V617F occurs with high frequency in myeloproliferative neoplasms. Further mutations affecting the Janus kinase family have been discovered mostly in leukaemias and in myeloproliferative neoplasms. Owing to their involvement in neoplasia, inflammatory diseases and in the immune response, Janus kinases are promising targets for kinase inhibitor therapy in these disease settings. Various quantitative assays including two newly developed screening assays were used to characterize the function of different small-molecule compounds in cells expressing Jak2V617F. A detailed comparative analysis of different Janus kinase inhibitors in our quantitative assays and the subsequent characterization of additional activities demonstrated for the first time that the most potent Jak2 inhibitor in our study, CEP701, also targets Aurora kinases. CEP701 shows a unique combination of both activities which is not found in other compounds also targeting Jak2. Furthermore, colony forming cell assays showed that Janus kinase 2 inhibitors preferentially suppressed the growth of erythroid colonies, whereas inhibitors of Aurora kinases preferentially blocked myeloid colony growth. CEP701 demonstrated a combined suppression of both colony types. Moreover, we show that combined application of a Janus and an Aurora kinase inhibitor recapitulated the effect observed for CEP701 but might allow for more flexibility in combining both activities in clinical settings, e.g. in the treatment of myeloproliferative neoplasms. The newly developed screening assays are high throughput compatible and allow an easy detection of new compounds with Janus kinase 2 inhibitory activity. © 2012 The Authors. Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
http://hdl.handle.net/10993/15766
10.1111/jcmm.12005
http://www.scopus.com/inward/record.url?eid=2-s2.0-84874368903&partnerID=40&md5=273da9b835d33b2bed18da25fda2e052
cited By (since 1996)0
Scopus

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