title: The current status and the future of JAK2 inhibitors for the treatment of myeloproliferative diseases.
abstract: Janus kinases (JAKs) are critical components of cytokine signaling pathways which regulate immunity, inflammation, hematopoiesis, growth, and development. The recent discovery of JAK2-activating mutations as a causal event in the majority of patients with Philadelphia chromosome negative (Ph-) myeloproliferative disorders (MPDs) prompted many pharmaceutical companies to develop JAK2-selective inhibitors for the treatment of MPDs. JAK2 inhibitors effectively reduce JAK2-driven phosphorylation of signal transducer and activator of transcription 5, and cell proliferation and cell survival in JAK2-activated cells in vitro and in vivo. Most inhibitors are currently being evaluated in patients with one form of MPD, myelofibrosis. Patients treated with these inhibitors experienced a rapid reduction of splenomegaly, significant improvement of constitutional symptoms, and increased daily activity with few adverse events. A partial reduction of JAK2V617F disease burden during the treatment with JAK2 inhibitors was also observed. The inhibitors appear to have a therapeutic benefit in the treatment of these disorders. The results of ongoing clinical trials will allow further evaluation of clinical benefits and safety of these compounds. In this review, the authors summarize the status of JAK2 inhibitors in development and discuss their benefits and challenges.
authors.affiliation: Rigel Pharmaceuticals Inc, 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. yhitoshi@rigel.com
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Hitoshi
authors.forename: Nan
authors.initials: N
authors.lastname: Lin
authors.forename: Donald G
authors.initials: DG
authors.lastname: Payan
authors.forename: Vadim
authors.initials: V
authors.lastname: Markovtsov
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D008969:Molecular Sequence Data; D009196:Myeloproliferative Disorders / Q000188:drug therapy*; D011487:Protein Conformation
chemical_list: D004791:Enzyme Inhibitors; C507924:JAK2 protein, human; D053614:Janus Kinase 2