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A Pharmacologic Inhibitor of the Protease Taspase1 Effectively Inhibits Breast and Brain Tumor Growth

  1. Author:
    Chen, D. Y.
    Lee, Y.
    Van Tine, B. A.
    Searleman, A. C.
    Westergard, T. D.
    Liu, H.
    Tu, H. C.
    Takeda, S.
    Dong, Y. Y.
    Piwnica-Worms, D. R.
    Oh, K. J.
    Korsmeyer, S. J.
    Hermone, A.
    Gussio, R.
    Shoemaker, R. H.
    Cheng, E. H. Y.
    Hsieh, J. J. D.

  2. Author Address

    [Liu, Han; Tu, Ho-Chou; Takeda, Shugaku; Dong, Yiyu; Cheng, Emily H. -Y.; Hsieh, James J. -D.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Cheng, Emily H. -Y.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Hsieh, James J. -D.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Chen, David Y.; Lee, Yishan; Van Tine, Brian A.; Searleman, Adam C.; Westergard, Todd D.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Piwnica-Worms, David R.] Washington Univ, Sch Med, Edward Mallinckrodt Inst Radiol, BRIGHT Inst,Mol Imaging Ctr, St Louis, MO 63110 USA. [Oh, Kyoung J.] Rosalind Franklin Univ, Chicago Med Sch, Dept Biochem & Mol Biol, N Chicago, IL USA. [Korsmeyer, Stanley J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hermone, Ann; Gussio, Richard] NCI, Informat Technol Branch, Dev Therapeut Program, Frederick, MD 21701 USA. [Shoemaker, Robert H.] NCI, Screening Technol Branch, Dev Therapeut Program, Frederick, MD 21701 USA.;Hsieh, JJD (reprint author), Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, Z801,415 E 68th St, New York, NY 10065 USA;hsiehj@mskcc.org
    1. Year: 2012
    2. Date: Feb
  2. Journal: Cancer Research
    1. 72
    2. 3
    3. Pages: 736-746
  4. Type of Article: Article
  5. ISSN: 0008-5472
  1. Abstract:

    The threonine endopeptidase Taspase1 has a critical role in cancer cell proliferation and apoptosis. In this study, we developed and evaluated small molecule inhibitors of Taspase1 as a new candidate class of therapeutic modalities. Genetic deletion of Taspase1 in the mouse produced no overt deficiencies, suggesting the possibility of a wide therapeutic index for use of Taspase1 inhibitors in cancers. We defined the peptidyl motifs recognized by Taspase1 and conducted a cell-based dual-fluorescent proteolytic screen of the National Cancer Institute diversity library to identify Taspase1 inhibitors (TASPIN). On the basis of secondary and tertiary screens the 4-[(4-arsonophenyl) methyl] phenyl] arsonic acid NSC48300 was determined to be the most specific active compound. Structure-activity relationship studies indicated a crucial role for the arsenic acid moiety in mediating Taspase1 inhibition. Additional fluorescence resonance energy transfer-based kinetic analysis characterized NSC48300 as a reversible, noncompetitive inhibitor of Taspase1 (Ki 4.22 mmol/ L). In the MMTV-neu mouse model of breast cancer and the U251 xenograft model of brain cancer, NSC48300 produced effective tumor growth inhibition. Our results offer an initial preclinical proof-of-concept to develop TASPINs for cancer therapy. Cancer Res; 72(3); 736-46. (C) 2011 AACR.

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External Sources

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  2. DOI: 10.1158/0008-5472.can-11-2584
  3. PMID: 22166309
  4. View record in Web of Science®
  5. WOS: 000300405900018

Library Notes

  1. Fiscal Year: FY2011-2012
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