title: Thiuram disulfides as pseudo-irreversible inhibitors of lymphoid tyrosine phosphatase.
abstract: We screened a small library of thiuram disulfides for inhibition of lymphoid tyrosine phosphatase (LYP) activity. The parent thiuram disulfide, disulfiram, inhibited LYP activity in vitro and in Jurkat T cells, whereas diethyldithiocarbamate failed to inhibit LYP at the concentrations tested. Compound 13, an N-(2-thioxothiazolidin-4-one) analogue, was found to be the most potent LYP inhibitor in this series, with an IC50 value of 3 μM. Compound 13 inhibits LYP pseudo-irreversibly, as evidenced by the time-dependence of inhibition, with a K(i) value of 1.1 μM and a k(inact) value of 0.004 s⁻¹. The inhibition of LYP by compound 13 could not be reversed significantly by incubation with glutathione or by prolonged dialysis, but could be partially reversed by incubation with dithiothreitol. Compound 13 also inhibited LYP activity in Jurkat T cells.
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Rhushikesh A
authors.initials: RA
authors.lastname: Kulkarni
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Stanford
authors.forename: Nadeem A
authors.initials: NA
authors.lastname: Vellore
authors.forename: Divya
authors.initials: D
authors.lastname: Krishnamurthy
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Bliss
authors.forename: Riccardo
authors.initials: R
authors.lastname: Baron
authors.forename: Nunzio
authors.initials: N
authors.lastname: Bottini
authors.forename: Amy M
authors.initials: AM
authors.lastname: Barrios
mesh_terms: D004220:Disulfides / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D011485:Protein Binding; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism; D013893:Thiram / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004220:Disulfides; D004791:Enzyme Inhibitors; D013844:Thiazoles; D013893:Thiram; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22
keywords: PTP; disulfiram; inhibitors; screening; thiuram disulfides