TG-101348 Tyrosine-Protein Kinase JAK2 Inhibitor Receptor-Type Tyrosine-Protein Kinase FLT3 Inhibitor Treatment of Myeloproliferative Diseases

TG-101348 is an orally available, small-molecule inhibitor of the tyrosine-protein kinase JAK2 (Janus kinase 2, JAK-2) that is under investigation for the treatment of myelofibrosis. Myelofibrosis and the related myeloproliferative neoplasms polycythemia vera and essential thrombocythemia are associated with the JAK2 V617F mutation, which causes hyperactivation of cytokine signaling pathways that control myeloid hematopoiesis. Several preclinical studies have demonstrated a pathogenic role for JAK2 V617F and the therapeutic potential of TG-101348 in polycythemia vera. In a phase I trial, TG-101348 reduced constitutional symptoms and splenomegaly in a JAK2 V617F-enriched population of intermediate- and high-risk myelofibrosis patients. Adverse events included nausea, vomiting, diarrhea, anemia and thrombocytopenia. A phase I/II extension study in the patients who experienced benefit from TG-101348 is in progress. Here we discuss the therapeutic rationale, pharmacokinetics, safety, efficacy and future potential of TG-101348.