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Thiuram Disulfides as Pseudo‐irreversible Inhibitors of Lymphoid Tyrosine Phosphatase
Author(s) -
Kulkarni Rhushikesh A.,
Stanford Stephanie M.,
Vellore Nadeem A.,
Krishnamurthy Divya,
Bliss Matthew R.,
Baron Riccardo,
Bottini Nunzio,
Barrios Amy M.
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300215
Subject(s) - chemistry , disulfiram , dithiothreitol , ic50 , jurkat cells , stereochemistry , protein tyrosine phosphatase , in vitro , incubation , medicinal chemistry , tyrosine , enzyme , biochemistry , t cell , immune system , immunology , biology
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 IC 50 value of 3 μ M . Compound 13 inhibits LYP pseudo‐irreversibly, as evidenced by the time‐dependence of inhibition, with a K i value of 1.1 μ M 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.