CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms

摘要: Activating alleles of Janus kinase 2 (JAK2) such as JAK2V617F are central to the pathogenesis myeloproliferative neoplasms (MPN), suggesting that small molecule inhibitors targeting JAK2 may be therapeutically useful. We have identified an aminopyrimidine derivative (CYT387), which inhibits JAK1, JAK2, and tyrosine (TYK2) at low nanomolar concentrations, with few additional targets. Between 0.5 1.5μM CYT387 caused growth suppression apoptosis in JAK2-dependent hematopoietic cell lines, while nonhematopoietic lines were unaffected. In a murine MPN model, normalized white counts, hematocrit, spleen size, restored physiologic levels inflammatory cytokines. Despite hematologic responses reduction allele burden, cells persisted recurred upon cessation treatment, unable eliminate cells, consistent preliminary results from clinical trials myelofibrosis. While benefit substantial, not least due cytokines symptomatic improvement, our data add increasing evidence inhibitor monotherapy malignant disease is curative, need for drug combinations optimally target cells.