CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms
| Autor: | Karl J. Aichberger, Thomas Bumm, Michael W. Deininger, Brian J. Druker, Christopher J. Burns, Lisa Wood, Jutta Deininger, Emmanuelle Fantino, Marc M. Loriaux, Jeffrey W. Tyner |
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| Rok vydání: | 2010 |
| Předmět: |
medicine.medical_treatment
Immunology Mutation Missense Apoptosis Biochemistry Proinflammatory cytokine Mice Polycythemia vera Myeloproliferative Disorders hemic and lymphatic diseases Cell Line Tumor medicine Animals Protein Kinase Inhibitors Mice Inbred BALB C Myeloid Neoplasia Janus kinase 2 Janus kinase 1 biology Essential thrombocythemia food and beverages Janus Kinase 1 Cell Biology Hematology Janus Kinase 2 medicine.disease Hematopoiesis Disease Models Animal Pyrimidines Cytokine Tyrosine kinase 2 Hematologic Neoplasms Benzamides Cancer research biology.protein Cytokines Drug Screening Assays Antitumor |
| Zdroj: | Blood. 115:5232-5240 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2009-05-223727 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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