In vivo mode of action of CYC116, a novel small molecule inhibitor of Aurora kinases and VEGFR2

Abstract

5645 Aurora kinases are key regulators of mitosis and cytokinesis and their upregulation has been associated with tumour genesis and progression. Their inhibition has been shown to be an efficacious therapeutic approach in human tumour xenograft models and several molecules are being pursued in clinical trials. Here we describe the in vivo mode of action of CYC116 - an orally bioavailable, novel kinase inhibitor currently evaluated in Phase I clinical trials. CYC116 is a potent Aurora A, B and C inhibitor (IC50 = 44, 19 and 69 nM respectively), which causes delayed entry into mitosis, defective mitotic spindle formation and cytokinesis, polyploidy and cell death. Additionally, CYC116 is a potent inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2) kinase in vitro (IC50 = 69 nM). CYC116 has shown antitumour activity in various solid tumour and leukaemia xenograft models.
 In vivo mode of action was studied in P388 mouse leukaemia, grown subcutaneously as a solid tumour. Immunohistochemistry and flow cytometry analyses clearly demonstrated Aurora kinase inhibition in the treated tumours. Dose- and time- dependent decrease in phospho Ser10 histone H3 and an increase in the population of polyploid tumour cells were observed. These effects of CYC116 correlated very well with the compound-induced decrease of tumour volume and leukaemia bone marrow infiltration. No significant effect on body weight or bone marrow cellularity was observed at the effective doses of CYC116. Tumour neovascularisation was also significantly reduced in a dose dependent manner. The results confirm that CYC116 acts as a dual mitotic and angiogenesis inhibitor in vivo, a combination of anti-proliferative mechanisms which could have therapeutic benefit in the clinic.
 Study was supported in part by grants MSM6198959216 and LC07017.