WP1066, a novel JAK2 inhibitor, suppresses proliferation and induces apoptosis in erythroid human cells carrying the JAK2 V617F mutation.
OBJECTIVE
The discovery of an activating somatic mutation in codon 617 of the gene encoding the Janus kinase (JAK)-2 (JAK2 V617F) in patients with myeloproliferative disorders has opened new avenues for the development of targeted therapies for these malignancies. However, no effective JAK2 inhibitors are currently available for clinical use.


METHODS
We investigated the activity of (E)-3(6-bromopyridin-2-yl)-2-cyano-N-(S0-1phenylethyl)acrylamide (WP1066), a novel analogue of the JAK2 inhibitor AG490, in JAK2 V617F-positive erythroleukemia HEL cells and in blood cells from patients with polycythemia vera.


RESULTS
We found that WP1066 significantly inhibited JAK2 and its downstream signal transducer and activator of transcription-3, signal transducer and activator of transcription-5, and extracellular signal-regulated kinase-1/2 pathways in a dose- and time-dependent manner. As a result, WP1066 concentrations in the low micromolar range induced time- and dose-dependent antiproliferative and proapoptotic effects in HEL cells. As expected, WP1066 inhibited the proliferation of peripheral blood hematopoietic progenitors of patients with polycythemia vera carrying the JAK2 V617F mutation in a dose-dependent manner.


CONCLUSIONS
Our data suggest that WP1066 is active both in vitro and ex vivo and should be further developed for the treatment of neoplasms expressing the JAK2 V617F mutation.
Verstovsek
Srdan
S
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Manshouri
Taghi
T
Quintás-Cardama
Alfonso
A
Harris
David
D
Cortes
Jorge
J
Giles
Francis J
FJ
Kantarjian
Hagop
H
Priebe
Waldemar
W
Estrov
Zeev
Z
D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D004915:Leukemia, Erythroblastic, Acute; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects; D009154:Mutation; D011087:Polycythemia Vera / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D020032:Tyrphostins / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011725:Pyridines; D020032:Tyrphostins; C519885:WP1066; D053614:Janus Kinase 2