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Potent and selective inhibition of JAK2 by the quinoxaline NVP-BSK805

Baffert, Fabienne and Blasco, Francesca and Brueggen, Josef and Chene, Patrick and De Pover, Alain and Drueckes, Peter and Erdmann, Dirk and Furet, Pascal and Gerspacher, Marc and Hofmann, Francesco and Lang, Marc and Ledieu, David and Nolan, Lynda and Pissot Soldermann, Carole and Regnier, Catherine and Ruetz, Stephan and Tavares, Gisele and Trappe, Joerg and Vangrevelinghe, Eric and Wartmann, Markus and Wyder, Lorenza and Radimerski, Thomas (2010) Potent and selective inhibition of JAK2 by the quinoxaline NVP-BSK805. Molecular Cancer Therapeutics, 9 (7). pp. 1945-1955. ISSN 1535-7163

Abstract

The recent discovery of an acquired activating point mutation in JAK2, substituting valine at amino acid position 617 for phenylalanine, has greatly improved our understanding of the molecular mechanism underlying chronic myeloproliferative neoplasms. Strikingly, the JAK2V617F mutation is found in nearly all patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia and from primary myelofibrosis. Thus, JAK2 represents a promising target for the treatment of myeloproliferative disorders and considerable efforts are ongoing to discover and develop inhibitors of the kinase. Here, we report potent inhibition of JAK2 wild type and JAK2V617F enzymes by a novel substituted quinoxaline, NVP-BSK805, which acts in an ATP-competitive manner. Within the JAK family, NVP-BSK805 displays more than twenty-fold selectivity towards JAK2 as well as excellent selectivity in broader kinase profiling. The compound blunts constitutive STAT5 phosphorylation in JAK2V617F-bearing cells, with concomitant suppression of cell proliferation and induction of apoptosis. In vivo, NVP-BSK805 exhibited good oral bioavailability and a long terminal half-life. The inhibitor was efficacious in suppressing leukemic cell spreading and splenomegaly in a Ba/F3 JAK2V617F cell-driven mouse mechanistic model. Furthermore, NVP-BSK805 potently suppressed recombinant human eryrthopoietin-induced polycythemia and extramedullary hematopoiesis in mice and rats.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Authors final version may be deposited on institutional website/ repository if required by institution
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/1787

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