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.
authors.affiliation: Department of Medicine, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Missouri, USA.
authors.forename: David Y
authors.initials: DY
authors.lastname: Chen
authors.forename: Yishan
authors.initials: Y
authors.lastname: Lee
authors.forename: Brian A
authors.initials: BA
authors.lastname: Van Tine
authors.forename: Adam C
authors.initials: AC
authors.lastname: Searleman
authors.forename: Todd D
authors.initials: TD
authors.lastname: Westergard
authors.forename: Han
authors.initials: H
authors.lastname: Liu
authors.forename: Ho-Chou
authors.initials: HC
authors.lastname: Tu
authors.forename: Shugaku
authors.initials: S
authors.lastname: Takeda
authors.forename: Yiyu
authors.initials: Y
authors.lastname: Dong
authors.forename: David R
authors.initials: DR
authors.lastname: Piwnica-Worms
authors.forename: Kyoung J
authors.initials: KJ
authors.lastname: Oh
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Korsmeyer
authors.forename: Ann
authors.initials: A
authors.lastname: Hermone
authors.forename: Richard
authors.initials: R
authors.lastname: Gussio
authors.forename: Robert H
authors.initials: RH
authors.lastname: Shoemaker
authors.forename: Emily H-Y
authors.initials: EH
authors.lastname: Cheng
authors.forename: James J-D
authors.initials: JJ
authors.lastname: Hsieh
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001152:Arsenicals / Q000494:pharmacology*; D001665:Binding Sites / Q000235:genetics; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D054852:Small Molecule Libraries; D023041:Xenograft Model Antitumor Assays
chemical_list: D000596:Amino Acids; D001152:Arsenicals; C571012:NSC48300; D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D010450:Endopeptidases; C480823:taspase1, human; C513958:taspase1, mouse