eprintid: 20549 rev_number: 24 userid: 1419 dir: disk0/00/02/05/49 datestamp: 2014-02-21 21:07:56 lastmod: 2021-06-12 22:55:51 status_changed: 2014-02-21 21:07:56 type: article metadata_visibility: show item_issues_count: 0 eprint_status: archive creators_name: Ducruet, AP creators_name: Rice, RL creators_name: Tamura, K creators_name: Yokokawa, F creators_name: Yokokawa, S creators_name: Wipf, P creators_name: Lazo, JS creators_email: creators_email: creators_email: creators_email: creators_email: creators_email: pwipf@pitt.edu creators_email: creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: PWIPF creators_id: title: Identification of new Cdc25 dual specificity phosphatase inhibitors in a targeted small molecule array ispublished: pub divisions: sch_as_chemistry full_text_status: public abstract: Dual specificity protein phosphatases (DSPases) are key regulators of signal transduction, oncogenesis and the cell cycle. Few potent or specific inhibitors of DSPases, however, are readily available for these pharmacological targets. We have used a combinatorial/parallel synthetic approach to rigidify the variable core region and modify the side chains of 4-(benzyl-(2-[2,5-diphenyl-oxazole-4-carbonyl)-amino]-ethyl)-carbamoyl)-2-decanoylamino butyric acid (or SC-ααδ9), which is the most active element in a previously described library of phosphatase inhibitors (Rice, R. L.; Rusnak, J. M.; Yokokawa, F.; Yokokawa, S.; Messner, D. J.; Boynton, A. L.; Wipf, P.; Lazo, J. S. Biochemistry 1997, 36, 15965). Several analogues were identified as effective inhibitors of the protein tyrosine phosphatase (PTPase) PTP1B and the DSPases VHR and Cdc25B2. Two compounds, FY3-αα09 and FY21-αα09, were partial competitive inhibitors of Cdc25B2 with K(i) values of 7.6±0.5 and 1.6±0.2 μM, respectively. FY21-αα09 possessed only moderate activity against PTP1B. Consistent with its in vitro anti-phosphatase activity, FY21-αα09 inhibited growth in MDA-MB-231 and MCF-7 human breast cancer cell lines. FY21-αα09 also inhibited the G2/M transition in tsFT210 cells, consistent with Cdc25B inhibition. Several architectural requirements for DSPase inhibition were revealed through modification of the side chain moieties or variable core region of the pharmacophore, which resulted in decreased compound potency. The structure of FY21-αα09 provides a useful platform from which additional potent and more highly selective phosphatase inhibitors might be generated. Copyright (C) 2000 Elsevier Science Ltd. date: 2000-06-01 date_type: published publication: Bioorganic and Medicinal Chemistry volume: 8 number: 6 pagerange: 1451 - 1466 refereed: TRUE issn: 0968-0896 id_number: 10.1016/S0968-0896(00)00069-9 pmid: 10896122 mesh_headings: Antineoplastic Agents--chemistry mesh_headings: Antineoplastic Agents--pharmacology mesh_headings: Enzyme Inhibitors--chemistry mesh_headings: Enzyme Inhibitors--pharmacology mesh_headings: Humans mesh_headings: Kinetics mesh_headings: Magnetic Resonance Spectroscopy mesh_headings: Mass Spectrometry mesh_headings: Stereoisomerism mesh_headings: Tumor Cells, Cultured mesh_headings: cdc25 Phosphatases--antagonists & inhibitors chemical_names: Antineoplastic Agents chemical_names: Enzyme Inhibitors chemical_names: cdc25 Phosphatases citation: Ducruet, AP and Rice, RL and Tamura, K and Yokokawa, F and Yokokawa, S and Wipf, P and Lazo, JS (2000) Identification of new Cdc25 dual specificity phosphatase inhibitors in a targeted small molecule array. Bioorganic and Medicinal Chemistry, 8 (6). 1451 - 1466. ISSN 0968-0896 document_url: http://d-scholarship-dev.library.pitt.edu/20549/1/licence.txt