A pharmacologic inhibitor of the protease Taspase1 effectively inhibits breast and brain tumor growth.

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 ╬╝mol/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.
AuthorsDavid 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
JournalCancer research (Cancer Res) Vol. 72 Issue 3 Pg. 736-46 (Feb 1 2012) ISSN: 1538-7445 [Electronic] United States
PMID22166309 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright©2011 AACR.
Chemical References
  • Amino Acids
  • Arsenicals
  • NSC48300
  • Protease Inhibitors
  • Small Molecule Libraries
  • Endopeptidases
  • taspase1, human
  • taspase1, mouse
  • Amino Acid Sequence
  • Amino Acids (genetics, metabolism)
  • Animals
  • Arsenicals (pharmacology)
  • Binding Sites (genetics)
  • Brain Neoplasms (enzymology, pathology, prevention & control)
  • Breast Neoplasms (enzymology, pathology, prevention & control)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Cells, Cultured
  • Endopeptidases (genetics, metabolism)
  • HEK293 Cells
  • Humans
  • Kinetics
  • Male
  • Mammary Neoplasms, Experimental (enzymology, pathology, prevention & control)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Protease Inhibitors (pharmacology)
  • Sequence Homology, Amino Acid
  • Small Molecule Libraries
  • Xenograft Model Antitumor Assays

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