going.28 5.0 Pan Aurora Kinase Inhibitors 5.1 VX 680/MK 0457 Discovered through a molecular screening campaign, VX 680/MK 0457 also potently inhibits Src and GSK3, Flt3, JAK2, BCR Abl and BCR Abl at nanomolar concentrations.103 The inhibition of a wide array of kinases stems from the ability to bind to non aurora kinases in their inactive conformations and preventing flt-3 inhibition activation.103 Many preclinical investigations with VX 680/MK 0457 were performed in cell lines and/or xenografts in animal models showing high degree of anti tumor activity. The tumor types investigated as single agent included ovarian104, renal cell carcinoma105, thyroid106, oral squamous cell107, CML 108,109,110, AML111, and MM112. Phenotypic changes induced by VX 680/MK 0457 indicated that synergy may be obtained by combining VX 680/MK 0457 with HDACI.
Vorinostat inhibits HDAC6 causing acetylation and disruption of heat shock protein GDC-0449 90. By inducing acetylation of hsp90, vorinostat inhibits the chaperone function of hsp90 leading to depleted aurora kinase levels in AML and CML cells.113 Several pre clinical studies combining vorinostat with VX 680/MK 0457 demonstrated additive or synergistic activity in AML113,114, colorectal cancer114, pancreatic cancer114, CML 113,115, Ph+ ALL116, and breast cancer117. Synergy was also seen when VX 680/MK 0457 is combined with chemotherapy agents or erlotinib, an orally available epidermal growth factor receptor antagonist, in preclinical studies of AML, CML, Ph+ ALL, and lung cancer.
118,119,120 An early phase I/II study in humans attempted to study not only the inhibitor effect of aurora kinase, but also the anti JAK2 effect by enrolling 15 patients including 6 with V617Fmutant JAK2 myeloproliferative disease.121 All patients received MK 0457 as a 5 day continuous infusion every 2�? weeks on a dose escalation schedule. Clinical correlates of CD34+ and peripheral blood morphonuclear cells were described, as well. Results were Green et al. Page 9 Recent Pat Anticancer Drug Discov. Author manuscript, available in PMC 2011 February 15. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript mixed, with 5 of 6 MPD patients displaying limited apoptosis and slight decrease in JAK2 transcripts. Three of 6 CML patients displayed no cytogenetic response and 3 exhibited a response.
Notably, one of the 6 CML patients received MK 0457 while in lymphoid blast crisis and displayed substantial apoptosis. In the 15 patients enrolled, virtually all of the in vitro markers for cell death were evident, but did not translate to in vivo findings. Another phase I study of 40 patients, including 16 CML patients , 2 Ph+ ALL , 13 with AML and 10 with rapidly progressing or transforming MPD evaluated dose escalation of MK 0457 as 5 day continuous infusion.122 Still in progress at time of publication, authors note that MTD was not reached despite using 24mg/m2/day as a 5 day continuous infusion, with only grade 1 nausea and alopecia observed. These interim results note that all 11 T315I BCR Abl CML patients and the T315I BCR Abl Ph+ALL patient experienced objective response. Six of 8 evaluable MPD patients also experienced objective responses.
A subsequent phase I study in refractory CML and Ph+ ALL patients studied the effect of combining dasatinib, a second generation BCR Abl inhibitor, with MK 0457 in 3 patients.123 All patients received dasatinib 70mg orally twice daily for 3 consecutive months. Patients who achieved major hematologic response received MK 0457 dosed at 64mg/m2/hr for 6 hours twice weekly. Patients who did not achieve MHR after 3 months of dasatinib received MK 0457 at a dose of 240mg/m2/day as continuous infusion for 5 days administered every 4 weeks. Both Ph+ ALL patients received biweekly treatment wit