title: Efficacious intermittent dosing of a novel JAK2 inhibitor in mouse models of polycythemia vera.
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.
authors.affiliation: Department of DMPK, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kraus
authors.forename: Yuxun
authors.initials: Y
authors.lastname: Wang
authors.forename: Dan
authors.initials: D
authors.lastname: Aleksandrowicz
authors.forename: Eric
authors.initials: E
authors.lastname: Bachman
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Szewczak
authors.forename: Deborah
authors.initials: D
authors.lastname: Walker
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Melaney
authors.initials: M
authors.lastname: Bouthillette
authors.forename: Kaleen M
authors.initials: KM
authors.lastname: Childers
authors.forename: Brian
authors.initials: B
authors.lastname: Dolinski
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Haidle
authors.forename: Johnny
authors.initials: J
authors.lastname: Kopinja
authors.forename: Linda
authors.initials: L
authors.lastname: Lee
authors.forename: Jongwon
authors.initials: J
authors.lastname: Lim
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Little
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Ma
authors.forename: Anjili
authors.initials: A
authors.lastname: Mathur
authors.forename: Jan-Rung
authors.initials: JR
authors.lastname: Mo
authors.forename: Erin
authors.initials: E
authors.lastname: O'Hare
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Otte
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Taoka
authors.forename: Wenxian
authors.initials: W
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Yin
authors.forename: Anna A
authors.initials: AA
authors.lastname: Zabierek
authors.forename: Weisheng
authors.initials: W
authors.lastname: Zhang
authors.forename: Shuxia
authors.initials: S
authors.lastname: Zhao
authors.forename: Joe
authors.initials: J
authors.lastname: Zhu
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Young
authors.forename: C Gary
authors.initials: CG
authors.lastname: Marshall
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004921:Erythropoietin / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D011087:Polycythemia Vera / Q000188:drug therapy*; D050799:STAT5 Transcription Factor / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D050799:STAT5 Transcription Factor; D004921:Erythropoietin; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2