title: Effect of NS-018, a selective JAK2V617F inhibitor, in a murine model of myelofibrosis.
abstract: A single somatic mutation, V617F, in Janus kinase 2 (JAK2) is one of the causes of myeloproliferative neoplasms (MPNs), including primary myelofibrosis, and the JAK2V617F mutant kinase is a therapeutic target in MPN. However, inhibition of wild-type (WT) JAK2 can decrease the erythrocyte or platelet (PLT) count. Our selective JAK2 inhibitor, NS-018, suppressed the growth of Ba/F3 cells harboring JAK2V617F more strongly than that of cells harboring WT JAK2. The 4.3-fold JAK2V617F selectivity of NS-018 is higher than the 1.0- to 2.9-fold selectivity of seven existing JAK2 inhibitors. NS-018 also inhibited erythroid colony formation in JAK2V617F transgenic mice at significantly lower concentrations than in WT mice. In keeping with the above results, in a JAK2V617F bone marrow transplantation mouse model with a myelofibrosis-like disease, NS-018 reduced leukocytosis and splenomegaly, improved bone marrow fibrosis and prolonged survival without decreasing the erythrocyte or PLT count in the peripheral blood. By exploring the X-ray co-crystal structure of NS-018 bound to JAK2, we identified unique hydrogen-bonding interactions between NS-018 and Gly993 as a plausible explanation for its JAK2V617F selectivity. These results suggest that NS-018 will have therapeutic benefit for MPN patients through both its efficacy and its reduced hematologic adverse effects.
authors.affiliation: 1] Department of Mechanical Science and Bioengineering, Graduate School of Engineering Science, Osaka University, Osaka, Japan [2] Discovery Research Laboratories, Nippon Shinyaku Co. Ltd, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nakaya
authors.affiliation: Department of Gastroenterology and Hematology, Faculty of Medicine, Miyazaki University, Miyazaki, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Shide
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co. Ltd, Kyoto, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Naito
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co. Ltd, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Niwa
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co. Ltd, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Horio
authors.affiliation: Department of Mechanical Science and Bioengineering, Graduate School of Engineering Science, Osaka University, Osaka, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Miyake
authors.affiliation: Department of Gastroenterology and Hematology, Faculty of Medicine, Miyazaki University, Miyazaki, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Shimoda