FMS-like tyrosine kinase 3 (FLT3) and Janus kinase 2 (JAK2) are tyrosine kinases that mediate cytokine signaling and are frequently mutated in cancers, particularly acute myeloid leukemia. Pacritinib is an inhibitor of both FLT3 and JAK2 (IC50s = 22 and 23 nM, respectively). It also blocks the activities of the FLT3 D835Y mutant, FLT3 with internal tandem duplications (ITDs), and JAK2 with a V617F substitution (IC50s = 6, 20-180, and 220 nM, respectively). Pacritinib also inhibits JAK1, JAK3, and TYK2 (IC50s = 1280, 520, and 50 nM, respectively). Pacritinib is orally bioavailable, inhibiting FLT3 and JAK2 signaling, tumor growth, and metastasis in xenografts in mice. It is synergistic with the histone deacetylase inhibitor pracinostat (also known as SB 939, ), decreasing cell proliferation and inducing apoptosis in cells carrying either the JAK2 V617F mutation or FLT3 with ITDs, both in vitro and in vivo. Pacritinib has potential in resolving hematological malignancies.
