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

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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.

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Acknowledgments

The authors would like to thank for their contributions to the SNS-314 project Darrin A. Allen, Subramanian Baskaran, Minna Bui, Emily J. Hanan, Stacey A. Heumann, Willard Lew, Robert S. McDowell, Johan D. Oslob, Wang Shen, Joshua C. Yoburn, Chul H. Yu and Min Zhong (Chemistry), Jeffrey Kumer and Tara Mullaney (Pharmacology), Tom O’Brien and Bradley Tangonan (Biology).

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Author notes

  1. Pietro Taverna

    Present address: SuperGen, Inc., 4140 Dublin Blvd., Suite 200, Dublin, CA, 94568, USA

Authors and Affiliations

  1. Department of Pharmacology, Sunesis Pharmaceuticals, Inc., 395 Oyster Point Blvd., South S. Francisco, CA, 94080, USA

    Jennifer P. Arbitrario, Marc J. Evanchik, Shannon O. Harris, Ute Hoch, Jennifer N. Hogan, Anthony R. Howlett, Jeffrey A. Silverman, Juli N. Teague & Pietro Taverna

  2. Department of Biology, Sunesis Pharmaceuticals, Inc., 395 Oyster Point Blvd., South S. Francisco, CA, 94080, USA

    Brian J. Belmont, W. Michael Flanagan, Raymond V. Fucini, Stig K. Hansen, Joni W. Lam, David E. Stockett & Kristin M. Zimmerman

  3. Department of Development Chemistry, Sunesis Pharmaceuticals, Inc., 395 Oyster Point Blvd., South S. Francisco, CA, 94080, USA

    Ahmad Hashash, Jeffrey W. Jacobs & Sean C. Ritchie

  4. Department of Protein Sciences and Structural Biology, Sunesis Pharmaceuticals, Inc., 395 Oyster Point Blvd., South S. Francisco, CA, 94080, USA

    Michael J. Romanowski

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  1. Jennifer P. Arbitrario
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Correspondence to Pietro Taverna.

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Arbitrario, J.P., Belmont, B.J., Evanchik, M.J. et al. SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo. Cancer Chemother Pharmacol 65, 707–717 (2010). https://doi.org/10.1007/s00280-009-1076-8

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  • DOI: https://doi.org/10.1007/s00280-009-1076-8

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