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

Cancer Chemother Pharmacol. 2010 Mar;65(4):707-17. doi: 10.1007/s00280-009-1076-8. Epub 2009 Aug 1.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / 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
  • Enzyme Inhibitors / pharmacology
  • Female
  • HCT116 Cells
  • HT29 Cells
  • HeLa Cells
  • Histones / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Mice, Nude
  • Molecular Structure
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Neoplasms / prevention & control*
  • Phenylurea Compounds / chemistry
  • Phenylurea Compounds / pharmacology*
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • 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