A pharmacologic inhibitor of the protease taspase1 effectively inhibits breast and brain tumor growth

David Y. Chen, Yishan Lee, Brian A. Van Tine, Adam C. Searleman, Todd D. Westergard, Han Liu, Ho Chou Tu, Shugaku Takeda, Yiyu Dong, David R. Piwnica-Worms, Kyoung J. Oh, Stanley J. Korsmeyer, Ann Hermone, Richard Gussio, Robert H. Shoemaker, Emily H.Y. Cheng, James J.D. Hsieh

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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.

Original languageEnglish
Pages (from-to)736-746
Number of pages11
JournalCancer research
Issue number3
StatePublished - Feb 1 2012


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