This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Verstovsek, S. Articles by Estrov, Z. Search for Related Content PubMed PubMed Citation Articles by Verstovsek, S. Articles by Estrov, Z.

WP1066, a Novel JAK2 Inhibitor, Suppresses Proliferation and Induces Apoptosis in Erythroid Human Cells Carrying the JAK2 V617F Mutation

Authors' Affiliations: Departments of ¹ Leukemia and ² Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Zeev Estrov, Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Unit 428, P.O. Box 301402, Houston, TX 77030. Phone: 713-794-1675; Fax: 713-745-0585; E-mail: zestrov{at}mdanderson.org.

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.