Ruxolitinib

Janus-associated kinases (JAKs) are cytoplasmic tyrosine kinases that are required for activating the signaling of certain cytokines and growth factor receptors.{19346,20362} A JAK2 gene fusion mutation, JAK2V617F, that causes unchecked activation of various growth factors and cytokines, has been linked to myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis.{21781} Ruxolitinib is a potent ATP mimetic that inhibits both JAK1 and JAK2 with IC50 values of 2.7 and 4.5 nM, respectively and is relatively less selective for JAK3 (IC50 = 322 nM).{21781} It can block interleukin-6 (IL-6) signaling (IC50 = 281 nM) and proliferation of JAK2V617F+ Ba/F3 cells (IC50 = 127 nM).{21782} In primary cultures, ruxolitinib preferentially suppresses erythroid progenitor colony formation from JAK2V617F+ polycythemia vera patients (IC50 = 67 nM) versus healthy donors (IC50 > 400 nM).{21782} In a mouse model of JAK2V617F+ MPN, 90 mg/kg ruxolitinib reduced splenomegaly, decreased circulating levels of IL-6 and TNF-a, eliminated neoplastic cells, and prolonged survival of the treated animals.{21782}