A pharmacologic inhibitor of the protease taspase1 effectively inhibits breast and brain tumor growth Journal Article
| Authors: | Chen, D. Y.; Lee, Y.; Van Tine, B. A.; Searleman, A. C.; Westergard, T. D.; Liu, H.; Tu, H. C.; Takeda, S.; Dong, 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. |
| Article Title: | A pharmacologic inhibitor of the protease taspase1 effectively inhibits breast and brain tumor growth |
| 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 (K i = 4.22 μmol/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. ©2011 AACR. |
| Keywords: | controlled study; protein expression; unclassified drug; human cell; gene deletion; drug efficacy; nonhuman; antineoplastic agent; protein motif; mouse; animal tissue; enzyme inhibition; breast cancer; protein degradation; animal experiment; animal model; drug structure; tumor xenograft; drug screening; drug synthesis; structure activity relation; cancer therapy; cancer inhibition; cell strain hek293; fluorescence resonance energy transfer; brain cancer; enzyme kinetics; [4 [(4 arsonophenyl)methyl]phenyl]arsonic acid; nsc 48300; taspase 1; threonine proteinase; threonine proteinase inhibitor |
| Journal Title: | Cancer Research |
| Volume: | 72 |
| Issue: | 3 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2012-02-01 |
| Start Page: | 736 |
| End Page: | 746 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-11-2584 |
| PROVIDER: | scopus |
| PUBMED: | 22166309 |
| PMCID: | PMC3325786 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 March 2012" - "CODEN: CNREA" - "Source: Scopus" |
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