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

• Published in: Clinical cancer research Vol. 14; no. 3; pp. 788 - 796
• Main Authors: Verstovsek, Srdan, Manshouri, Taghi, Quintás-Cardama, Alfonso, Harris, David, Cortes, Jorge, Giles, Francis J., Kantarjian, Hagop, Priebe, Waldemar, Estrov, Zeev
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.02.2008
• Subjects: Amino Acid Substitution; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Cell Division - drug effects; Cell Line; Cell Line, Tumor; Cell Survival - drug effects; Enzyme Inhibitors - pharmacology; HEL cells; Humans; JAK2 mutation; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - genetics; Leukemia, Erythroblastic, Acute; Medical sciences; Megakaryocytes - cytology; Megakaryocytes - drug effects; Mutation; Pharmacology. Drug treatments; polycythemia vera; Polycythemia Vera - pathology; Pyridines - pharmacology; Tyrphostins - pharmacology; WP1066; Human; Cell proliferation; Erythroid cell; Enzyme; Cell death; JAK2 protein tyrosine kinase; Transferases; Genetics; Inhibitor; Mutation; Protein-tyrosine kinase; Apoptosis
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-0524

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.