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.

• Authors: 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
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 3 Pg. 736-46 (Feb 01 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22166309 (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