Cancer Chemotherapy and Pharmacology

, Volume 65, Issue 4, pp 707–717

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

  • 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
Original Article

DOI: 10.1007/s00280-009-1076-8

Cite this article as:
Arbitrario, J.P., Belmont, B.J., Evanchik, M.J. et al. Cancer Chemother Pharmacol (2010) 65: 707. doi:10.1007/s00280-009-1076-8

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.

Keywords

Aurora kinase Experimental therapeutics Small-molecule kinase inhibitors Anti-tumor activity Xenografts 

Supplementary material

280_2009_1076_MOESM1_ESM.doc (33 kb)
Supplemental information (DOC 33 kb)

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Jennifer P. Arbitrario
    • 1
  • Brian J. Belmont
    • 2
  • Marc J. Evanchik
    • 1
  • W. Michael Flanagan
    • 2
  • Raymond V. Fucini
    • 2
  • Stig K. Hansen
    • 2
  • Shannon O. Harris
    • 1
  • Ahmad Hashash
    • 3
  • Ute Hoch
    • 1
  • Jennifer N. Hogan
    • 1
  • Anthony R. Howlett
    • 1
  • Jeffrey W. Jacobs
    • 3
  • Joni W. Lam
    • 2
  • Sean C. Ritchie
    • 3
  • Michael J. Romanowski
    • 4
  • Jeffrey A. Silverman
    • 1
  • David E. Stockett
    • 2
  • Juli N. Teague
    • 1
  • Kristin M. Zimmerman
    • 2
  • Pietro Taverna
    • 1
    • 5
  1. 1.Department of PharmacologySunesis Pharmaceuticals, Inc.South S. FranciscoUSA
  2. 2.Department of BiologySunesis Pharmaceuticals, Inc.South S. FranciscoUSA
  3. 3.Department of Development ChemistrySunesis Pharmaceuticals, Inc.South S. FranciscoUSA
  4. 4.Department of Protein Sciences and Structural BiologySunesis Pharmaceuticals, Inc.South S. FranciscoUSA
  5. 5.SuperGen, Inc.DublinUSA

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