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Disabling the mitotic spindle and tumor growth by targeting a cavity-induced allosteric site of survivin

Oncogene volume 31, pages 1938–1948 (2012)Cite this article

Abstract

Survivin is a member of the inhibitor of apoptosis protein family and has an essential role in mitosis. Survivin is overexpressed in a large variety of human cancers and represents an attractive target for cancer therapy. Epidermal growth factor receptor and Her/neu-transformed human tumors in particular exhibit high levels of survivin. The survivin protein forms dimers through a conserved region that is critical for subcellular localization and biological functions of the protein. We identified small molecules that target a specific cavity adjacent to the survivin dimerization surfaces. S12, a lead compound identified in the screen, can bind to the survivin protein at the intended target site. Moreover, S12 alters spindle formation, causing mitotic arrest and cell death, and inhibits tumor growth in vitro and in vivo. Cell death occurs in premetaphase stage following mitotic arrest and is not a consequence of general toxicity. Thus, the study validates a novel therapeutic target site in the survivin protein and provides a promising strategy to develop a new class of therapeutic small molecules for the treatment of human cancers.

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Acknowledgements

We thank Dr Robert L Margolis (the Sanford-Burnham Medical Research Institute, La Jolla, CA, USA) for providing the pGEX-survivin plasmid. This work was supported by grants from the Abramson Family Cancer Research Institute of the University of Pennsylvania, The National Cancer Institute, the Breast Cancer Research Foundation and the Nidus Laboratories, Inc.

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Author notes

  1. Q Wang

    Present address: 3Current address: Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.,

  2. M I Greene and Q Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    A Berezov, Z Cai, J A Freudenberg, H Zhang, X Cheng, T Thompson, R Murali, M I Greene & Q Wang

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  1. A Berezov
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Correspondence to M I Greene or Q Wang.

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Berezov, A., Cai, Z., Freudenberg, J. et al. Disabling the mitotic spindle and tumor growth by targeting a cavity-induced allosteric site of survivin. Oncogene 31, 1938–1948 (2012). https://doi.org/10.1038/onc.2011.377

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