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The antisignaling agent SC-ααδ9, 4-(benzyl-(2-[(2,5- diphenyloxazole-4-carbonyl)amino]ethyl)carbamoyl)-2-decanoylaminobutyric acid, is a structurally unique phospholipid analogue with phospholipase C inhibitory activity

Vogt, A and Pestell, KE and Day, BW and Lazo, JS and Wipf, P (2002) The antisignaling agent SC-ααδ9, 4-(benzyl-(2-[(2,5- diphenyloxazole-4-carbonyl)amino]ethyl)carbamoyl)-2-decanoylaminobutyric acid, is a structurally unique phospholipid analogue with phospholipase C inhibitory activity. Molecular Cancer Therapeutics, 1 (11). 885 - 892. ISSN 1535-7163

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Abstract

Phospholipids and lipid second messengers mediate mitogenic signal transduction and oncogenesis, but there have been few successful examples of small molecules that affect biologically important phospholipid metabolism. Here we investigated the actions of a previously described antitumor agent, 4-(benzyl-(2-[(2,5-diphenyloxazole-4-carbonyl)amino]ethyl)carbamoyl) -2-decanoylaminobutyric acid (SC-ααδ9), which has antisignaling properties, on phospholipases. Although SC-ααδ9 had been shown to be a potent and selective inhibitor of the Cdc25 family of dual-specificity phosphatases, many of its cellular effects are not readily reconciled with phosphatase inhibition. Molecular modeling studies suggested that SC-ααδ9 shared several structural features with membrane phospholipids. Enzyme inhibition studies in vitro revealed that SC-ααδ9 was a potent inhibitor of phospholipase C (PLC; IC50 = 25 μM) but did not inhibit phospholipase D activity at concentrations up to 100 μM. In H-ras (Q61L)-transformed Rat-1 fibroblasts with constitutively elevated levels of phosphorylated extracellular signal-regulated kinase (Erk), SC-ααδ9 inhibited both proliferation and oncogenic Erk activation at concentrations that inhibited PLC in vitro. A SC-ααδ9 congener that lacked antiproliferative activity also did not inhibit PLC in vitro. In the PLC-dependent scratch wound healing model, SC-ααδ9 was 10-fold more potent than the phosphatidylcholine-specific PLC inhibitor D-609. We propose that the structural resemblance of SC-ααδ9 to phospholipids allows it to inhibit cellular PLC, thereby providing a possible molecular mechanism for SC-ααδ9's effects on oncogenic Erk activation. © 2002 American Association for Cancer Research.


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Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Vogt, Aavogt@pitt.eduAVOGT
Pestell, KE
Day, BW
Lazo, JS
Wipf, Ppwipf@pitt.eduPWIPF
Date: 1 September 2002
Date Type: Publication
Journal or Publication Title: Molecular Cancer Therapeutics
Volume: 1
Number: 11
Page Range: 885 - 892
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 1535-7163
MeSH Headings: Alkaline Phosphatase--metabolism; Animals; Blotting, Western; Bridged Compounds--pharmacology; Cell Division--drug effects; Cell Movement--drug effects; Cell Survival--drug effects; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors--pharmacology; Fibroblasts--drug effects; Fibroblasts--metabolism; Genes, ras--genetics; Inhibitory Concentration 50; Mitogen-Activated Protein Kinases--metabolism; Models, Chemical; Models, Molecular; Oxazoles--chemistry; Oxazoles--pharmacology; Phospholipase D--metabolism; Phospholipids--chemistry; Phospholipids--metabolism; Rats; Signal Transduction; Thiones--pharmacology; Time Factors; Type C Phospholipases--antagonists & inhibitors; Type C Phospholipases--metabolism; Wound Healing--drug effects
PubMed ID: 12481409
Date Deposited: 31 Jul 2014 20:50
Last Modified: 02 Feb 2019 15:56
URI: http://d-scholarship.pitt.edu/id/eprint/22266

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