title: R723, a selective JAK2 inhibitor, effectively treats JAK2V617F-induced murine myeloproliferative neoplasm.
abstract: The activating mutations in JAK2 (including JAK2V617F) that have been described in patients with myeloproliferative neoplasms (MPNs) are linked directly to MPN pathogenesis. We developed R723, an orally bioavailable small molecule that inhibits JAK2 activity in vitro by 50% at a concentration of 2nM, while having minimal effects on JAK3, TYK2, and JAK1 activity. R723 inhibited cytokine-independent CFU-E growth and constitutive activation of STAT5 in primary hematopoietic cells expressing JAK2V617F. In an anemia mouse model induced by phenylhydrazine, R723 inhibited erythropoiesis. In a leukemia mouse model using Ba/F3 cells expressing JAK2V617F, R723 treatment prolonged survival and decreased tumor burden. In V617F-transgenic mice that closely mimic human primary myelofibrosis, R723 treatment improved survival, hepatosplenomegaly, leukocytosis, and thrombocytosis. R723 preferentially targeted the JAK2-dependent pathway rather than the JAK1- and JAK3-dependent pathways in vivo, and its effects on T and B lymphocytes were mild compared with its effects on myeloid cells. Our preclinical data indicate that R723 has a favorable safety profile and the potential to become an efficacious treatment for patients with JAK2V617F-positive MPNs.
authors.affiliation: Department of Gastroenterology and Hematology, Faculty of Medicine, Miyazaki University, Kiyotake, Miyazaki, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Shide
authors.forename: Takuro
authors.initials: T
authors.lastname: Kameda
authors.forename: Vadim
authors.initials: V
authors.lastname: Markovtsov
authors.forename: Haruko K
authors.initials: HK
authors.lastname: Shimoda
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tonkin
authors.forename: Shuling
authors.initials: S
authors.lastname: Fang
authors.forename: Chian
authors.initials: C
authors.lastname: Liu
authors.forename: Marina
authors.initials: M
authors.lastname: Gelman
authors.forename: Wayne
authors.initials: W
authors.lastname: Lang
authors.forename: Jason
authors.initials: J
authors.lastname: Romero
authors.forename: John
authors.initials: J
authors.lastname: McLaughlin
authors.forename: Somasekhar
authors.initials: S
authors.lastname: Bhamidipati
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Clough
authors.forename: Caroline
authors.initials: C
authors.lastname: Low
authors.forename: Andrea
authors.initials: A
authors.lastname: Reitsma
authors.forename: Stacey
authors.initials: S
authors.lastname: Siu
authors.forename: Polly
authors.initials: P
authors.lastname: Pine
authors.forename: Gary
authors.initials: G
authors.lastname: Park
authors.forename: Allan
authors.initials: A
authors.lastname: Torneros
authors.forename: Matt
authors.initials: M
authors.lastname: Duan
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
authors.forename: Donald G
authors.initials: DG
authors.lastname: Payan
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Hitoshi
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimoda
mesh_terms: D000743:Anemia, Hemolytic / Q000139:chemically induced; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002460:Cell Line; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004920:Erythropoiesis / Q000187:drug effects; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics; D007964:Leukocytosis / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009154:Mutation / Q000187:drug effects; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D053614:Janus Kinase 2