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Departments of Pharmacology [A. V., K. E. P., J. S. L.], Pharmaceutical Sciences [B. W. D], and Chemistry [B. W. D., P. W.], University of Pittsburgh, Pittsburgh, Pennsylvania 15261

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-9), which has antisignaling properties, on phospholipases. Although SC-9 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-9 shared several structural features with membrane phospholipids. Enzyme inhibition studies in vitro revealed that SC-9 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-9 inhibited both proliferation and oncogenic Erk activation at concentrations that inhibited PLC in vitro. A SC-9 congener that lacked antiproliferative activity also did not inhibit PLC in vitro. In the PLC-dependent scratch wound healing model, SC-9 was 10-fold more potent than the phosphatidylcholine-specific PLC inhibitor D-609. We propose that the structural resemblance of SC-9 to phospholipids allows it to inhibit cellular PLC, thereby providing a possible molecular mechanism for SC-9’s effects on oncogenic Erk activation.

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