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Cell-active dual specificity phosphatase inhibitors identified by high-content screening

Vogt, A and Cooley, KA and Brisson, M and Tarpley, MG and Wipf, P and Lazo, JS (2003) Cell-active dual specificity phosphatase inhibitors identified by high-content screening. Chemistry and Biology, 10 (8). 733 - 742. ISSN 1074-5521

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Phosphorylation of extracellular signal-regulated kinase (Erk) is tightly controlled by dual specificity phosphatases (DSPases), but few inhibitors of Erk dephosphorylation have been identified. Using a high-content, fluorescence-based cellular assay and the National Cancer Institute's 1990 agent Diversity Set, we identified ten compounds (0.5%) that significantly increased phospho-Erk cytonuclear differences in intact cells. Three of the ten positive compounds inhibited the mitogen-activated protein kinase phosphatase-3 (MKP-3/PYST-1) in vitro without affecting VHR or PTP1B phosphatases. The most potent inhibitor of MKP-3 had an IC50 of <10 μM and inhibited MKP-3 in a novel, fluorescence-based multiparameter chemical complementation assay. These results suggest that the phospho-Erk nuclear accumulation assay may be a useful tool to discover DSPase inhibitors with biological activity.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Vogt, A
Cooley, KA
Brisson, M
Tarpley, MG
Wipf, Ppwipf@pitt.eduPWIPF
Lazo, JS
Date: 1 August 2003
Date Type: Publication
Journal or Publication Title: Chemistry and Biology
Volume: 10
Number: 8
Page Range: 733 - 742
DOI or Unique Handle: 10.1016/s1074-5521(03)00170-4
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 1074-5521
MeSH Headings: Animals; Antineoplastic Agents--pharmacology; Benzofurans--pharmacology; Drug Evaluation, Preclinical--methods; Dual Specificity Phosphatase 6; Enzyme Activation; Enzyme Inhibitors--analysis; Fluorescent Antibody Technique--methods; HeLa Cells; Humans; Imidazoles--pharmacology; Mice; NIH 3T3 Cells; Phosphorylation; Protein Tyrosine Phosphatases--antagonists & inhibitors; Protein Tyrosine Phosphatases--metabolism; Substrate Specificity; cdc25 Phosphatases--antagonists & inhibitors; cdc25 Phosphatases--metabolism
PubMed ID: 12954332
Date Deposited: 30 Jan 2014 18:19
Last Modified: 22 Jun 2021 12:55


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