MK-0457 Is a Novel Aurora Kinase and Janus Kinase 2 (JAK2) Inhibitor with Activity in Transformed JAK2-Positive Myeloproliferative Disease (MPD).

MK-0457 (VX-680) was developed as a small-molecule inhibitor of Aurora kinases A, B, and C (K_i,app = 0.66–18 nM). Recent screening for additional kinase activity shows that MK-0457 inhibits JAK-2 with an IC50 of 123 nM for wildtype JAK2 and 295 nM for the JAK2 V617F activating mutation. Based on these in vitro findings, eleven patients with documented JAK2-mutated myeloproliferative disorders (MPDs), including 2 patients with prior MPD progressing to AML, were treated with MK-0457 at either 20, 24 or 28 mg/m²/hr administered by a continuous 5-day intravenous infusion every 3 weeks. The age range was 37– 83 (median 64); 5 (45%) patients were male and performance status was 0 or 1 in 10 (91%) patients. Five (45%) patients were previously splenectomized and 2 (33%) of the non-splenectomized patients had splenomegaly present at baseline. Two (18%) patients had diploid cytogenetics, eight (73%) were pseudodiploid with varying abnormalities and one (9%) had a -17 abnormality. One patient with hepatosplenomegaly at enrollment experienced complete resolution of hepatomegaly and >50% reduction in splenomegaly with a single cycle of therapy. Of the 10 (91%) patients starting therapy with a normal or increased absolute neutrophil count (ANC), all experienced grade 3 or 4 neutropenia during the study period. Transient reductions in platelet counts of patients with normal or elevated baseline platelets were also seen. Six of 7 (86%) patients with serial JAK2 testing had gradual, yet steady reductions in percentage of PCR product with the V617F mutation. MK-0457 is worthy of further exploration at lower doses (20mg/m²/hr) which are more suitable for chronic administration in patients with less aggressive disease, in contrast to patients with AML transformation of JAK2-mutated MPD in which higher, more myelosuppressive doses may be warranted.