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Discovery and biological evaluation of a new family of potent inhibitors of the dual specificity protein phosphatase Cdc25

Lazo, JS and Aslan, DC and Southwick, EC and Cooley, KA and Ducruet, AP and Joo, B and Vogt, A and Wipf, P (2001) Discovery and biological evaluation of a new family of potent inhibitors of the dual specificity protein phosphatase Cdc25. Journal of Medicinal Chemistry, 44 (24). 4042 - 4049. ISSN 0022-2623

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Abstract

The Cdc25 dual specificity phosphatases have central roles in coordinating cellular signaling processes and cell proliferation, but potent and selective inhibitors are lacking. We experimentally examined the 1990 compound National Cancer Institute Diversity Set and then computationally selected from their 140 000 compound repository 30 quinolinediones of which 8 had in vitro mean inhibitory concentrations < 1 μM. The most potent was 6-chloro-7-(2-morpholin-4-ylethylamino)quinoline-5,8-dione (NSC 663284), which was 20- and 450-fold more selective against Cdc25B2 as compared with VHR or PTP1B phosphatases, respectively. NSC 663284 exhibited mixed competitive kinetics against Cdc25A, Cdc25B2, and Cdc25C with Ki values of 29, 95, and 89 nM, respectively. As compared with NSC 663284, the regioisomer 7-chloro-6-(2-morpholin-4-ylethylamino)quinoline-5,8-dione was 3-fold less active against Cdc25B2 in vitro and less potent as a growth inhibitor of human breast cancer cells. Computational electrostatic potential mapping suggested the need for an electron-deficient 7-position for maximal inhibitor activity. Using a chemical complementation assay, we found that NSC 663284 blocked cellular Erk dephosphorylation caused by ectopic Cdc25A expression.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Lazo, JSlazo@pitt.eduLAZO
Aslan, DC
Southwick, EC
Cooley, KA
Ducruet, AP
Joo, B
Vogt, A
Wipf, Ppwipf@pitt.eduPWIPF
Date: 22 November 2001
Date Type: Publication
Journal or Publication Title: Journal of Medicinal Chemistry
Volume: 44
Number: 24
Page Range: 4042 - 4049
DOI or Unique Handle: 10.1021/jm0102046
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0022-2623
MeSH Headings: Antineoplastic Agents--chemical synthesis; Antineoplastic Agents--chemistry; Antineoplastic Agents--pharmacology; Cell Division--drug effects; Drug Screening Assays, Antitumor; Enzyme Inhibitors--chemical synthesis; Enzyme Inhibitors--chemistry; Enzyme Inhibitors--pharmacology; Humans; Kinetics; Mitogen-Activated Protein Kinases--metabolism; Models, Molecular; Quinolines--chemical synthesis; Quinolines--chemistry; Quinolines--pharmacology; Quinolones--chemical synthesis; Quinolones--chemistry; Quinolones--pharmacology; Quinones--chemical synthesis; Quinones--chemistry; Quinones--pharmacology; Recombinant Proteins--antagonists & inhibitors; Recombinant Proteins--metabolism; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured; cdc25 Phosphatases--antagonists & inhibitors; cdc25 Phosphatases--metabolism
Other ID: 10.1021/jm0102046
PubMed ID: 11708908
Date Deposited: 13 Feb 2014 19:18
Last Modified: 02 Feb 2019 15:56
URI: http://d-scholarship.pitt.edu/id/eprint/20472

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