SCH 1473759, a novel Aurora inhibitor, demonstrates enhanced anti-tumor activity in combination with taxanes and KSP inhibitors

• Published in: Cancer chemotherapy and pharmacology Vol. 68; no. 4; pp. 923 - 933
• Main Authors: Basso, Andrea D., Liu, Ming, Gray, Kimberly, Tevar, Seema, Lee, Suining, Liang, Lianzhu, Ponery, Abdul, Smith, Elizabeth B., Monsma, Frederick J., Yu, Tao, Zhang, Yonglian, Kerekes, Angela D., Esposite, Sara, Xiao, Yushi, Tagat, Jayaram R., Hicklin, Daniel J., Kirschmeier, Paul
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-10-2011; Springer; Springer Nature B.V
• Subjects: Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antitumor agents; Aurora kinase; Aurora Kinase A; Aurora Kinases; Biological and medical sciences; Cancer Research; Cell death; Cell Line, Tumor; DNA; Drug Administration Schedule; Female; Humans; Imidazoles - administration & dosage; Imidazoles - pharmacology; Kinesin - antagonists & inhibitors; Male; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Nude; Mitosis; Neoplasms - drug therapy; Neoplasms - pathology; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Pyrazines - administration & dosage; Pyrazines - pharmacology; siRNA; taxanes; Taxoids - administration & dosage; Tumor cell lines; Tumors; Xenograft Model Antitumor Assays; Xenografts; Aurora; KSP; Taxane; Antineoplastic agent; Drug combination; Taxane derivatives; Inhibitor; Serine/threonine-protein kinase 6; Biological activity
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-011-1568-1

Purpose
Aurora kinases are required for orderly progression of cells through mitosis, and inhibition of these kinases by siRNA or small molecule inhibitors results in cell death. We previously reported the synthesis of SCH 1473759, a novel sub-nanomolar Aurora A/B inhibitor.
Methods
We utilized SCH 1473759 and a panel of tumor cell lines and xenograft models to gain knowledge about optimal dosing schedule and chemotherapeutic combinations for Aurora A/B inhibitors.
Results
SCH 1473759 was active against a large panel of tumor cell lines from different tissue origin and genetic backgrounds. Asynchronous cells required 24-h exposure to SCH 1473759 for maximal induction of >4 N DNA content and inhibition of cell growth. However, following taxane- or KSP inhibitor-induced mitotic arrest, less than 4-h exposure induced >4 N DNA content. This finding correlated with the ability of SCH 1473759 to accelerate exit from mitosis in response to taxane- and KSP inhibitor-induced arrest. We tested various dosing schedules in vivo and demonstrated SCH 1473759 dose- and schedule-dependent anti-tumor activity in four human tumor xenograft models. Further, the efficacy was enhanced in combination with taxanes and found to be most efficacious when SCH 1473759 was dosed 12-h post-taxane treatment.
Conclusions
SCH 1473759 demonstrated potent mechanism-based activity, and activity was shown to be enhanced in combination with taxanes and KSP inhibitors. This information may be useful for optimizing the clinical efficacy of Aurora inhibitors.