HOMEPRODUCTSSERVICESCOMPANYCONTACTFAQResearchDictionaryPharmaMobileSign Up FREE or Login

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 ╬╝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
Topics
  • 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

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!


Choose Username:
Email:
Password:
Verify Password: