1. Efficacious Intermittent Dosing of a Novel JAK2 Inhibitor in Mouse Models of Polycythemia Vera
- Author
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Melaney Bouthillette, Lin Xu, Brian Dolinski, C. Gary Marshall, Andrew M. Haidle, Kevin D. Little, Hong Yin, Anjili Mathur, Linda Lee, Shuxia Zhao, Alexander A. Szewczak, Weisheng Zhang, Yanhong Ma, Brandon M. Taoka, Erin O’Hare, Wenxian Wang, Eric Bachman, Jan-Rung Mo, Johnny E. Kopinja, Jongwon Lim, Joe Zhu, Anna A. Zabierek, Deborah Walker, Kaleen M. Childers, Jonathan R. Young, Yuxun Wang, Manfred Kraus, Dan Aleksandrowicz, and Ryan D. Otte
- Subjects
Myeloid ,Mouse ,lcsh:Medicine ,Signal transduction ,Hematologic Cancers and Related Disorders ,Mice ,Molecular cell biology ,Polycythemia vera ,hemic and lymphatic diseases ,Tyrosine Kinase Signaling Cascade ,Drug Discovery ,STAT5 Transcription Factor ,Enzyme Inhibitors ,lcsh:Science ,Polycythemia Vera ,Multidisciplinary ,Janus kinase 2 ,Animal Models ,Hematology ,Flow Cytometry ,Signaling Cascades ,medicine.anatomical_structure ,Medicine ,Research Article ,medicine.drug ,Drugs and Devices ,Drug Research and Development ,Signaling in cellular processes ,Blotting, Western ,Spleen ,Biology ,Colony-Forming Units Assay ,Model Organisms ,medicine ,Animals ,Humans ,Erythropoietin ,Cell Proliferation ,STAT signaling family ,Myeloproliferative Disorders ,Dose-Response Relationship, Drug ,lcsh:R ,Janus Kinase 2 ,medicine.disease ,Hematopoiesis ,Mice, Inbred C57BL ,Apoptosis ,Cell culture ,Immunology ,Cancer research ,biology.protein ,lcsh:Q ,Bone marrow - Abstract
A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV) harbor a Val617→Phe activating mutation in the Janus kinase 2 (JAK2) gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO)-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition. MRLB-11055 effectively prevented EPO-induced STAT5 activation in the peripheral blood of acutely dosed mice, and could prevent EPO-induced splenomegaly and erythrocytosis in chronically dosed mice. In a bone marrow reconstituted JAK2V617F-luciferase murine PV model, MRLB-11055 rapidly reduced the burden of JAK2V617F-expressing cells from both the spleen and the bone marrow. Using real-time in vivo imaging, we examined the kinetics of disease regression and resurgence, enabling the development of an intermittent dosing schedule that achieved significant reductions in both erythroid and myeloid populations with minimal impact on lymphoid cells. Our studies provide a rationale for the use of non-continuous treatment to provide optimal therapy for PV patients.
- Published
- 2012
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