Potent and selective inhibition of polycythemia by the quinoxaline JAK2 inhibitor NVP-BSK805.
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.
Baffert
Fabienne
F
Disease Area Oncology, Novartis Institutes for BioMedical Research, 4057 Basel, Switzerland.
Régnier
Catherine H
CH
De Pover
Alain
A
Pissot-Soldermann
Carole
C
Tavares
Gisele A
GA
Blasco
Francesca
F
Brueggen
Josef
J
Chène
Patrick
P
Drueckes
Peter
P
Erdmann
Dirk
D
Furet
Pascal
P
Gerspacher
Marc
M
Lang
Marc
M
Ledieu
David
D
Nolan
Lynda
L
Ruetz
Stephan
S
Trappe
Joerg
J
Vangrevelinghe
Eric
E
Wartmann
Markus
M
Wyder
Lorenza
L
Hofmann
Francesco
F
Radimerski
Thomas
T
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
C553194:NVP-BSK805; D011810:Quinoxalines; D050799:STAT5 Transcription Factor; D000255:Adenosine Triphosphate; D053614:Janus Kinase 2