TY - JOUR
T1 - WP1066, a novel JAK2 inhibitor, suppresses proliferation and induces apoptosis in erythroid human cells carrying the JAK2 V617F mutation
AU - Verstovsek, Srdan
AU - Manshouri, Taghi
AU - Quintás-Cardama, Alfonso
AU - Harris, David
AU - Cortes, Jorge
AU - Giles, Francis J.
AU - Kantarjian, Hagop
AU - Priebe, Waldemar
AU - Estrov, Zeev
PY - 2008/2/1
Y1 - 2008/2/1
N2 - Purpose: 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. Experimental Design: 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.
AB - Purpose: 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. Experimental Design: 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.
UR - http://www.scopus.com/inward/record.url?scp=38949086558&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=38949086558&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-07-0524
DO - 10.1158/1078-0432.CCR-07-0524
M3 - Article
C2 - 18245540
AN - SCOPUS:38949086558
SN - 1078-0432
VL - 14
SP - 788
EP - 796
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 3
ER -