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

Jeffrey Tyner, Thomas G. Bumm, Jutta Deininger, Lisa Wood, Karl J. Aichberger, Marc Loriaux, Brian Druker, Christopher J. Burns, Emmanuelle Fantino, Michael W. Deininger

Research output: Contribution to journalArticle

149 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5232-5240
Number of pages9
JournalBlood
Volume115
Issue number25
DOIs
StatePublished - Jun 24 2010

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Janus Kinase 2
Cytokines
Neoplasms
TYK2 Kinase
Alleles
Cells
Cell Line
Primary Myelofibrosis
Withholding Treatment
Drug Combinations
N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
Hematocrit
Phosphotransferases
Spleen
Cell Count
Clinical Trials
Apoptosis
Derivatives
Molecules
Growth

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. / Tyner, Jeffrey; Bumm, Thomas G.; Deininger, Jutta; Wood, Lisa; Aichberger, Karl J.; Loriaux, Marc; Druker, Brian; Burns, Christopher J.; Fantino, Emmanuelle; Deininger, Michael W.

In: Blood, Vol. 115, No. 25, 24.06.2010, p. 5232-5240.

Research output: Contribution to journalArticle

Tyner, Jeffrey ; Bumm, Thomas G. ; Deininger, Jutta ; Wood, Lisa ; Aichberger, Karl J. ; Loriaux, Marc ; Druker, Brian ; Burns, Christopher J. ; Fantino, Emmanuelle ; Deininger, Michael W. / CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. In: Blood. 2010 ; Vol. 115, No. 25. pp. 5232-5240.
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