eprintid: 20472 rev_number: 24 userid: 1419 dir: disk0/00/02/04/72 datestamp: 2014-02-13 19:18:29 lastmod: 2021-06-12 22:55:47 status_changed: 2014-02-13 19:18:29 type: article metadata_visibility: show item_issues_count: 0 eprint_status: archive creators_name: Lazo, JS creators_name: Aslan, DC creators_name: Southwick, EC creators_name: Cooley, KA creators_name: Ducruet, AP creators_name: Joo, B creators_name: Vogt, A creators_name: Wipf, P creators_email: lazo@pitt.edu creators_email: creators_email: creators_email: creators_email: creators_email: creators_email: creators_email: pwipf@pitt.edu creators_id: LAZO creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: PWIPF title: Discovery and biological evaluation of a new family of potent inhibitors of the dual specificity protein phosphatase Cdc25 ispublished: pub divisions: sch_as_chemistry full_text_status: public 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. date: 2001-11-22 date_type: published publication: Journal of Medicinal Chemistry volume: 44 number: 24 pagerange: 4042 - 4049 refereed: TRUE issn: 0022-2623 id_number: 10.1021/jm0102046 other_id: 10.1021/jm0102046 pmid: 11708908 mesh_headings: Antineoplastic Agents--chemical synthesis mesh_headings: Antineoplastic Agents--chemistry mesh_headings: Antineoplastic Agents--pharmacology mesh_headings: Cell Division--drug effects mesh_headings: Drug Screening Assays, Antitumor mesh_headings: Enzyme Inhibitors--chemical synthesis mesh_headings: Enzyme Inhibitors--chemistry mesh_headings: Enzyme Inhibitors--pharmacology mesh_headings: Humans mesh_headings: Kinetics mesh_headings: Mitogen-Activated Protein Kinases--metabolism mesh_headings: Models, Molecular mesh_headings: Quinolines--chemical synthesis mesh_headings: Quinolines--chemistry mesh_headings: Quinolines--pharmacology mesh_headings: Quinolones--chemical synthesis mesh_headings: Quinolones--chemistry mesh_headings: Quinolones--pharmacology mesh_headings: Quinones--chemical synthesis mesh_headings: Quinones--chemistry mesh_headings: Quinones--pharmacology mesh_headings: Recombinant Proteins--antagonists & inhibitors mesh_headings: Recombinant Proteins--metabolism mesh_headings: Stereoisomerism mesh_headings: Structure-Activity Relationship mesh_headings: Tumor Cells, Cultured mesh_headings: cdc25 Phosphatases--antagonists & inhibitors mesh_headings: cdc25 Phosphatases--metabolism chemical_names: Antineoplastic Agents chemical_names: Enzyme Inhibitors chemical_names: NSC 663284 chemical_names: Quinolines chemical_names: Quinolones chemical_names: Quinones chemical_names: Recombinant Proteins chemical_names: Mitogen-Activated Protein Kinases chemical_names: cdc25 Phosphatases citation: 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 document_url: http://d-scholarship-dev.library.pitt.edu/20472/1/licence.txt