Abstract 1648: SCH 1473759, a novel aurora inhibitor, demonstrates enhanced antitumor activity in combination with taxanes and KSP inhibitors

Abstract

Abstract Aurora kinases are required for orderly progression of cells through mitosis. Inhibition of these kinases by siRNA or a small molecule inhibitors results in aberrant endoreduplication and cell death. SCH 1473759 is a novel Aurora inhibitor with potent mechanism based cell activity. The compound is active against a large panel of tumor cell lines from different tissue origin and genetic backgrounds. We found that asynchronous cells require 24 hour exposure to SCH 1473759 to induce maximal endoreduplication and cell kill. However, following a taxane or KSP inhibitor mitotic arrest, less than 4-hour exposure was sufficient to induce endoreduplication. This finding correlated with the ability of SCH 1473759 to accelerate exit from mitosis in response to taxane and KSP induced arrest, but not that of a nocodazole arrest. SCH 1473759 demonstrated single agent biomarker and anti-tumor activity in A2780 ovarian xenograft models. Further, efficacy was enhanced in combination with taxotere and found to be most efficacious when SCH 1473759 was dosed 12-hours post taxotere. These findings could have clinical implications for the development of Aurora inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1648.