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Identification of a potent and selective pharmacophore for Cdc25 dual specificity phosphatase inhibitors

Lazo, JS and Nemoto, K and Pestell, KE and Cooley, K and Southwick, EC and Mitchell, DA and Furey, W and Gussio, R and Zaharevitz, DW and Joo, B and Wipf, P (2002) Identification of a potent and selective pharmacophore for Cdc25 dual specificity phosphatase inhibitors. Molecular Pharmacology, 61 (4). 720 - 728. ISSN 0026-895X

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Small molecules provide powerful tools to interrogate biological pathways but many important pathway participants remain refractory to inhibitors. For example, Cdc25 dual-specificity phosphatases regulate mammalian cell cycle progression and are implicated in oncogenesis, but potent and selective inhibitors are lacking for this enzyme class. Thus, we evaluated 10,070 compounds in a publicly available chemical repository of the National Cancer Institute for in vitro inhibitory activity against oncogenic, full-length, recombinant human Cdc25B. Twenty-one compounds had mean inhibitory concentrations of <1 μM; >75% were quinones and >40% were of the paranaphthoquinone structural type. Most notable was NSC 95397 (2,3-bis-[2-hydroxyethylsulfanyl]-[1,4]naphthoquinone), which displayed mixed inhibition kinetics with in vitro Ki values for Cdc25A, -B, and -C of 32, 96, and 40 nM, respectively. NSC 95397 was more potent than any inhibitor of dual specificity phosphatases described previously and 125- to 180-fold more selective for Cdc25A than VH1-related dual-specificity phosphatase or protein tyrosine phosphatase 1b, respectively. Modification of the bis-thioethanol moiety markedly decreased enzyme inhibitory activity, indicating its importance for bioactivity. NSC 95397 showed significant growth inhibition against human and murine carcinoma cells and blocked G2/M phase transition. A potential Cdc25 site of interaction was postulated based on molecular modeling with these quinones. We propose that inhibitors based on this chemical structure could serve as useful tools to probe the biological function of Cdc25.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Lazo, JSlazo@pitt.eduLAZO
Nemoto, K
Pestell, KE
Cooley, K
Southwick, EC
Mitchell, DA
Furey, Wfureyw@pitt.eduFUREYW0000-0002-7788-0689
Gussio, R
Zaharevitz, DW
Joo, B
Wipf, Ppwipf@pitt.eduPWIPF
Date: 15 April 2002
Date Type: Publication
Journal or Publication Title: Molecular Pharmacology
Volume: 61
Number: 4
Page Range: 720 - 728
DOI or Unique Handle: 10.1124/mol.61.4.720
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0026-895X
MeSH Headings: Amino Acid Motifs; Binding Sites; Cell Cycle--drug effects; Cell Cycle Proteins--antagonists & inhibitors; Cell Cycle Proteins--chemistry; Cell Division--drug effects; Drug Evaluation, Preclinical; Enzyme Inhibitors--chemistry; Enzyme Inhibitors--pharmacology; Humans; Kinetics; Models, Molecular; Naphthoquinones--chemistry; Naphthoquinones--pharmacology; Tumor Cells, Cultured; cdc25 Phosphatases--antagonists & inhibitors; cdc25 Phosphatases--chemistry
Other ID: 10.1124/mol.61.4.720
PubMed ID: 11901209
Date Deposited: 12 Feb 2014 23:41
Last Modified: 04 Oct 2021 21:55


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