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Discovery and characterization of novel small molecule inhibitors of human Cdc25B dual specificity phosphatase

Brisson, M and Nguyen, T and Vogt, A and Yalowich, J and Giorgianni, A and Tobi, D and Bahar, I and Stephenson, CRJ and Wipf, P and Lazo, JS (2004) Discovery and characterization of novel small molecule inhibitors of human Cdc25B dual specificity phosphatase. Molecular Pharmacology, 66 (4). 824 - 833. ISSN 0026-895X

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Abstract

Cdc25A and Cdc25B dual-specificity phosphatases are key regulators of cell cycle transition and proliferation. They have oncogenic properties and are overexpressed in many human tumors. Because selective Cdc25 phosphatase inhibitors would be valuable biological tools and possible therapeutic agents, we have assayed a small molecule library for in vitro inhibition of Cdc25. We now report the identification of two new structurally distinct classes of Cdc25 inhibitors with cellular activity. The cyclopentaquinoline 3a,4,5,9b-tetrahydro- 3H-cyclopenta[c]quinoline-4,8-dicarboxylic acid (5661118) and the naphthofurandione 3-benzoyl-naphtho[1,2-b]furan-4,5-dione (5169131) had in vitro IC 50 values of 2.5 to 11 μM against recombinant Cdc25 and were less potent inhibitors of other phosphatases. Unlike 5661118, 5169131 caused reversible inhibition of Cdc25B and displayed competitive inhibitor kinetics. No growth inhibitory activity was seen with 5661118, whereas 10 to 30 μM 5169131 caused G 1/ S and G 2 /M arrest. We also found that 5169131 inhibited human PC-3 prostate and MDA-MB-435 breast cancer cell proliferation. Concentration-dependent Tyr15 hyperphosphorylation was seen on cyclin-dependent kinase with a 1-h 5169131 treatment, consistent with Cdc25 inhibition. Cells resistant to DNA toposiomerase II inhibitors were as sensitive to 5169131 as parental cells, indicating that this quinone compound does not inhibit topoisomerase II in vivo. Molecular modeling was used to predict a potential interaction site between the inhibitor and Cdc25B and to provide insights as to the molecular origins of the experimental observations. Based on its kinetic profile and cellular activity, we suggest that 5169131 could be an excellent tool for further studies on the cellular roles of Cdc25.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Brisson, M
Nguyen, T
Vogt, A
Yalowich, J
Giorgianni, A
Tobi, D
Bahar, Ibahar@pitt.eduBAHAR
Stephenson, CRJ
Wipf, Ppwipf@pitt.eduPWIPF
Lazo, JS
Date: 1 October 2004
Date Type: Publication
Journal or Publication Title: Molecular Pharmacology
Volume: 66
Number: 4
Page Range: 824 - 833
DOI or Unique Handle: 10.1124/mol.104.001784
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0026-895X
MeSH Headings: Cell Cycle--drug effects; Cell Cycle Proteins--antagonists & inhibitors; Cell Division--drug effects; Enzyme Inhibitors--chemical synthesis; Enzyme Inhibitors--isolation & purification; Furans--chemical synthesis; Furans--isolation & purification; Humans; Naphthoquinones--chemical synthesis; Naphthoquinones--isolation & purification; Substrate Specificity; Tumor Cells, Cultured; cdc25 Phosphatases--antagonists & inhibitors
PubMed ID: 15231869
Date Deposited: 30 Jan 2014 18:16
Last Modified: 19 Mar 2019 11:55
URI: http://d-scholarship.pitt.edu/id/eprint/20422

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