WP1066, a novel JAK2 inhibitor, suppresses proliferation and induces apoptosis in erythroid human cells carrying the JAK2 V617F mutation

Srdan Verstovsek, Taghi Manshouri, Alfonso Quintás-Cardama, David Harris, Jorge Cortes, Francis J. Giles, Hagop Kantarjian, Waldemar Priebe, Zeev Estrov

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)788-796
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number3
DOIs
StatePublished - Feb 1 2008
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Verstovsek, S., Manshouri, T., Quintás-Cardama, A., Harris, D., Cortes, J., Giles, F. J., Kantarjian, H., Priebe, W., & Estrov, Z. (2008). WP1066, a novel JAK2 inhibitor, suppresses proliferation and induces apoptosis in erythroid human cells carrying the JAK2 V617F mutation. Clinical Cancer Research, 14(3), 788-796. https://doi.org/10.1158/1078-0432.CCR-07-0524