TYROSINE-PROTEIN KINASE JAK2 INHIBITORS FOR THE TREATMENT OF MYELOPROLIFERATIVE NEOPLASMS

Tyrosine-protein kinase JAK2, a cytoplasmic tyrosine kinase, plays a critical role in hematopoiesis and activating mutations in this kinase are associated with a number of hematological disorders. Recently, several somatic point mutations, such as JAK2 V617F, that constitutively activate the JAK/STAT signaling pathway have been identified in the majority of patients with myeloproliferative neoplasms (MPNs). This discovery made JAK2 an attractive molecule for therapeutic targeting in MPNs and has been the driving force behind the development of small-mclecule inhibitors that specifically target JAK2. Since then, many different JAK2 inhibitors have been identified using a variety of screening techniques and have been characterized preclinically, as well as clinically. This review article discusses the efficacy of small-molecule inhibitors for therapeutic targeting of JAK2 in MPNs, with special focus on inhibitors with recently reported results from preliminary phase I/II clinical trials. Based an the analysis of reports from these initial studies, we attempt to identify potential problems and issues that stand in the way of the development of a successful targeted therapy for JAK2-mediated disorders.