Investigational Janus kinase inhibitors

Introduction: Dysregulation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is central to the pathophysiology of myeloproliferative neoplasms (MPN). Small molecule inhibitors of JAK family members are currently under investigation for the treatment of MPN. Of these, ruxolitinib has received approval for clinical use in myelofibrosis in the United States and Europe. Areas covered: The clinical results and future development program of major JAK inhibitors, including ruxolitinib, CYT387, SAR302503, lestaurtinib, pacritinib, XL-019, LY2784544, BMS-911453, AZD1480 and NS-018 are reviewed. Expert opinion: JAK inhibitors are effective in relieving organomegaly (splenomegaly and hepatomegaly) and constitutional symptoms of myelofibrosis and some modulate inflammatory cytokines. However, they have little impact on disease burden and bone marrow fibrosis. The relationship between clinical efficacy, toxicity profile and specificity of JAK family member inhibition (i.e., JAK2 specific vs JAK1/JAK2 active) is poorly defined. Novel resistance mechanisms including heterodimerization of JAK2 with other JAK family members have been described. It is likely that the future lies in the use of rational drug combinations that target multiple signaling pathways.