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.