RT Journal Article SR Electronic T1 Potent and Selective Inhibition of Polycythemia by the Quinoxaline JAK2 Inhibitor NVP-BSK805 JF Molecular Cancer Therapeutics JO Mol Cancer Ther FD American Association for Cancer Research SP 1945 OP 1955 DO 10.1158/1535-7163.MCT-10-0053 VO 9 IS 7 A1 Baffert, Fabienne A1 Régnier, Catherine H. A1 De Pover, Alain A1 Pissot-Soldermann, Carole A1 Tavares, Gisele A. A1 Blasco, Francesca A1 Brueggen, Josef A1 Chène, Patrick A1 Drueckes, Peter A1 Erdmann, Dirk A1 Furet, Pascal A1 Gerspacher, Marc A1 Lang, Marc A1 Ledieu, David A1 Nolan, Lynda A1 Ruetz, Stephan A1 Trappe, Joerg A1 Vangrevelinghe, Eric A1 Wartmann, Markus A1 Wyder, Lorenza A1 Hofmann, Francesco A1 Radimerski, Thomas YR 2010 UL http://mct.aacrjournals.org/content/9/7/1945.abstract AB 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 primary myelofibrosis. Thus, JAK2 represents a promising target for the treatment of myeloproliferative neoplasms and considerable efforts are ongoing to discover and develop inhibitors of the kinase. Here, we report potent inhibition of JAK2V617F and JAK2 wild-type enzymes by a novel substituted quinoxaline, NVP-BSK805, which acts in an ATP-competitive manner. Within the JAK family, NVP-BSK805 displays more than 20-fold selectivity towards JAK2 in vitro, 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 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 erythropoietin-induced polycythemia and extramedullary erythropoiesis in mice and rats. Mol Cancer Ther; 9(7); 1945–55. ©2010 AACR.