title: Cooperative effects of Janus and Aurora kinase inhibition by CEP701 in cells expressing Jak2V617F.
abstract: 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.
authors.affiliation: Life Sciences Research Unit - Signal Transduction Laboratory, University of Luxembourg, Luxembourg, Luxembourg.
authors.forename: Karoline
authors.initials: K
authors.lastname: Gäbler
authors.forename: Catherine
authors.initials: C
authors.lastname: Rolvering
authors.forename: Jakub
authors.initials: J
authors.lastname: Kaczor
authors.forename: René
authors.initials: R
authors.lastname: Eulenfeld
authors.forename: Sergio Álvarez
authors.initials: SÁ
authors.lastname: Méndez
authors.forename: Guy
authors.initials: G
authors.lastname: Berchem
authors.forename: Valérie
authors.initials: V
authors.lastname: Palissot
authors.forename: Iris
authors.initials: I
authors.lastname: Behrmann
authors.forename: Claude
authors.initials: C
authors.lastname: Haan
mesh_terms: D064127:Aurora Kinases; D015153:Blotting, Western; D002227:Carbazoles / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003114:Colony-Forming Units Assay; D005434:Flow Cytometry; D005663:Furans; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D002227:Carbazoles; D005663:Furans; C119379:lestaurtinib; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases