CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms

Tyner, Jeffrey W., Bumm, Thomas G., Deininger, Jutta, Wood, Lisa, Aichberger, Karl J., Loriaux, Marc M., Druker, Brian J., Burns, Christopher J., Fantino, Emmanuelle and Deininger, Michael W. (2010) CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood, 115 25: 5232-5240. doi:10.1182/blood-2009-05-223727


Author Tyner, Jeffrey W.
Bumm, Thomas G.
Deininger, Jutta
Wood, Lisa
Aichberger, Karl J.
Loriaux, Marc M.
Druker, Brian J.
Burns, Christopher J.
Fantino, Emmanuelle
Deininger, Michael W.
Title CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms
Journal name Blood   Check publisher's open access policy
ISSN 0006-4971
Publication date 2010-06-01
Year available 2010
Sub-type Article (original research)
DOI 10.1182/blood-2009-05-223727
Open Access Status Not yet assessed
Volume 115
Issue 25
Start page 5232
End page 5240
Total pages 9
Place of publication United States
Publisher American Society of Hematology
Language eng
Formatted abstract
Activating alleles of Janus kinase 2 (JAK2) such as JAK2V617F are central to the pathogenesis of myeloproliferative neoplasms (MPN), suggesting that small molecule inhibitors targeting JAK2 may be therapeutically useful. We have identified an aminopyrimidine derivative (CYT387), which inhibits JAK1, JAK2, and tyrosine kinase 2 (TYK2) at low nanomolar concentrations, with few additional targets. Between 0.5 and 1.5μM CYT387 caused growth suppression and apoptosis in JAK2-dependent hematopoietic cell lines, while nonhematopoietic cell lines were unaffected. In a murine MPN model, CYT387 normalized white cell counts, hematocrit, spleen size, and restored physiologic levels of inflammatory cytokines. Despite the hematologic responses and reduction of the JAK2V617F allele burden, JAK2V617F cells persisted and MPN recurred upon cessation of treatment, suggesting that JAK2 inhibitors may be unable to eliminate JAK2V617F cells, consistent with preliminary results from clinical trials of JAK2 inhibitors in myelofibrosis. While the clinical benefit of JAK2 inhibitors may be substantial, not the least due to reduction of inflammatory cytokines and symptomatic improvement, our data add to increasing evidence that kinase inhibitor monotherapy of malignant disease is not curative, suggesting a need for drug combinations to optimally target the malignant cells.
Keyword Acute Myeloid-Leukemia
Tyrosine Kinase Jak2
Polycythemia-Vera
Activating Mutation
Essential Thrombocythemia
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID HL082978-01
1R21NR010363
J2758-B12
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: ERA 2012 Admin Only
School of Medicine Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 127 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 131 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Mon, 03 Oct 2011, 21:27:09 EST by System User on behalf of Child Health Research Centre