title: Potent and selective inhibition of polycythemia by the quinoxaline JAK2 inhibitor NVP-BSK805.
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 JAK2(V617F) 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 JAK2(V617F) 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 JAK2(V617F)-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 JAK2(V617F) cell-driven mouse mechanistic model. Furthermore, NVP-BSK805 potently suppressed recombinant human erythropoietin-induced polycythemia and extramedullary erythropoiesis in mice and rats.
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, 4057 Basel, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Baffert
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Régnier
authors.forename: Alain
authors.initials: A
authors.lastname: De Pover
authors.forename: Carole
authors.initials: C
authors.lastname: Pissot-Soldermann
authors.forename: Gisele A
authors.initials: GA
authors.lastname: Tavares
authors.forename: Francesca
authors.initials: F
authors.lastname: Blasco
authors.forename: Josef
authors.initials: J
authors.lastname: Brueggen
authors.forename: Patrick
authors.initials: P
authors.lastname: Chène
authors.forename: Peter
authors.initials: P
authors.lastname: Drueckes
authors.forename: Dirk
authors.initials: D
authors.lastname: Erdmann
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.forename: Marc
authors.initials: M
authors.lastname: Gerspacher
authors.forename: Marc
authors.initials: M
authors.lastname: Lang
authors.forename: David
authors.initials: D
authors.lastname: Ledieu
authors.forename: Lynda
authors.initials: L
authors.lastname: Nolan
authors.forename: Stephan
authors.initials: S
authors.lastname: Ruetz
authors.forename: Joerg
authors.initials: J
authors.lastname: Trappe
authors.forename: Eric
authors.initials: E
authors.lastname: Vangrevelinghe
authors.forename: Markus
authors.initials: M
authors.lastname: Wartmann
authors.forename: Lorenza
authors.initials: L
authors.lastname: Wyder
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Radimerski
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004920:Erythropoiesis / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D020014:K562 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011086:Polycythemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017434:Protein Structure, Tertiary; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013163:Splenomegaly / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control
chemical_list: C553194:NVP-BSK805; D011810:Quinoxalines; D050799:STAT5 Transcription Factor; D000255:Adenosine Triphosphate; D053614:Janus Kinase 2