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Identification of new Cdc25 dual specificity phosphatase inhibitors in a targeted small molecule array

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

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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.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Ducruet, AP
Rice, RL
Tamura, K
Yokokawa, F
Yokokawa, S
Wipf, Ppwipf@pitt.eduPWIPF
Lazo, JS
Date: 1 June 2000
Date Type: Publication
Journal or Publication Title: Bioorganic and Medicinal Chemistry
Volume: 8
Number: 6
Page Range: 1451 - 1466
DOI or Unique Handle: 10.1016/s0968-0896(00)00069-9
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0968-0896
MeSH Headings: Antineoplastic Agents--chemistry; Antineoplastic Agents--pharmacology; Enzyme Inhibitors--chemistry; Enzyme Inhibitors--pharmacology; Humans; Kinetics; Magnetic Resonance Spectroscopy; Mass Spectrometry; Stereoisomerism; Tumor Cells, Cultured; cdc25 Phosphatases--antagonists & inhibitors
PubMed ID: 10896122
Date Deposited: 21 Feb 2014 21:07
Last Modified: 22 Jun 2021 12:55
URI: http://d-scholarship.pitt.edu/id/eprint/20549

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