SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo.

Abstract

PURPOSE:

The Aurora family of serine/threonine kinases (Aurora-A, Aurora-B, and Aurora-C) plays a key role in cells orderly progression through mitosis. Elevated expression levels of Aurora kinases have been detected in a high percentage of melanoma, colon, breast, ovarian, gastric, and pancreatic tumors. We characterized the biological and pharmacological properties of SNS-314, an ATP-competitive, selective, and potent inhibitor of Aurora kinases.

METHODS:

We studied the biochemical potency and selectivity of SNS-314 to inhibit Aurora kinases A, B, and C. The inhibition of cellular proliferation induced by SNS-314 was evaluated in a broad range of tumor cell lines and correlated to inhibition of histone H3 phosphorylation, inhibition of cell-cycle progression, increase in nuclear content and cell size, loss of viability, and induction of apoptosis. The dose and administration schedule of SNS-314 was optimized for in vivo efficacy in mouse xenograft models of human cancer.

RESULTS:

In the HCT116 human colon cancer xenograft model, administration of 50 and 100 mg/kg SNS-314 led to dose-dependent inhibition of histone H3 phosphorylation for at least 10 h, indicating effective Aurora-B inhibition in vivo. HCT116 tumors from animals treated with SNS-314 showed potent and sustained responses including reduction of phosphorylated histone H3 levels, increased caspase-3 and appearance of increased nuclear size. The compound showed significant tumor growth inhibition in a dose-dependent manner under a variety of dosing schedules including weekly, bi-weekly, and 5 days on/9 days off.

CONCLUSIONS:

SNS-314 is a potent small-molecule inhibitor of Aurora kinases developed as a novel anti-cancer therapeutic agent for the treatment of diverse human malignancies.

• Authors: Jennifer P Arbitrario, Brian J Belmont, Marc J Evanchik, W Michael Flanagan, Raymond V Fucini, Stig K Hansen, Shannon O Harris, Ahmad Hashash, Ute Hoch, Jennifer N Hogan, Anthony R Howlett, Jeffrey W Jacobs, Joni W Lam, Sean C Ritchie, Michael J Romanowski, Jeffrey A Silverman, David E Stockett, Juli N Teague, Kristin M Zimmerman, Pietro Taverna
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 65 Issue 4 Pg. 707-17 (Mar 2010) ISSN: 1432-0843 [Electronic] Germany
• PMID: 19649632 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Histones
• Phenylurea Compounds
• SNS 314
• Thiazoles
• AURKB protein, human
• AURKC protein, human
• Aurka protein, mouse
• Aurkb protein, mouse
• Aurkc protein, mouse
• Aurora Kinase A
• Aurora Kinase B
• Aurora Kinase C
• Aurora Kinases
• Protein Serine-Threonine Kinases
• Caspase 3

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Aurora Kinase A
• Aurora Kinase B
• Aurora Kinase C
• Aurora Kinases
• Caspase 3 (metabolism)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemistry, pharmacology)
• Female
• HCT116 Cells
• HT29 Cells
• HeLa Cells
• Histones (metabolism)
• Humans
• Inhibitory Concentration 50
• Mice
• Mice, Nude
• Molecular Structure
• Neoplasms (metabolism, pathology, prevention & control)
• Phenylurea Compounds (chemistry, pharmacology)
• Phosphorylation (drug effects)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Thiazoles (chemistry, pharmacology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays