Lestaurtinib

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 disorders.{21781} Lestaurtinib is a staurosporine analog that potently inhibits JAK2 kinase (IC50 = 1 nM) and downstream targets STAT5 (IC50 = 10-30 nM) and STAT3 in a human erythroleukemic cell line expressing the JAK2V617F mutation.{21781,21796} It has been used to reduce tumor growth in a xenograft model of pancreatic ductal adenocarcinoma, to inhibit cell growth in a trk-B overexpressing neuroblastoma xenograft model, and to block proliferation and induce apoptosis in Hodgkin lymphoma cell lines.{21794,21797,21795} Lestaurtinib has since been reported to potently inhibit the epigenetic kinase PRK1 in vitro (IC50 = 8.6 nM), inducing hypophosphorylation of histone H3 threonine 11 and blocking androgen-dependent gene expression in prostate cancer cells at a concentration of 5 ?M.{21798}