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Vol. 287, Issue 2, 806-813, November 1998

Disruption of Insulin-Like Growth Factor-1 Signaling and Down-Regulation of Cdc2 by SC-alpha alpha delta 9, a Novel Small Molecule Antisignaling Agent Identified in a Targeted Array Library

Andreas Vogt, Robert L. Rice, Catherine E. Settineri, Fumiaki Yokokawa, Shiho Yokokawa, Peter Wipf and John S. Lazo

Department of Pharmacology, School of Medicine (A.V., R.L.R., C.E.S., J.S.L.), Department of Chemistry, Combinatorial Chemistry Center (F.Y., S.Y., P.W.), and Pittsburgh Cancer Institute (P.W., J.S.L.), University of Pittsburgh, Pittsburgh, Pennsylvania

We previously reported the generation of a library of hydrophobic oxazole-based small molecules designed as inhibitors of phosphatases involved in cellular signaling and cell cycle control. One member of the targeted array library, 4-(benzyl-(2-[(2,5-diphenyl-oxazole-4-carbonyl)-amino]-ethyl)-carbamoyl)-2-decanoylamino butyric acid (SC-alpha alpha delta 9), inhibited cell growth in the G0/G1 phase of the cell cycle. To investigate potential mechanisms for SC-alpha alpha delta 9 antiproliferative activity, we have used mouse embryonic fibroblasts transformed with simian virus 40 large T antigen mouse embryonic fibroblasts as a model system for a malignant phenotype that depends on overexpression of cell cycle regulators and autocrine stimulation by insulin-like growth factor-1. Structure-activity relationship studies with SC-alpha alpha delta 9 and four library congeners demonstrated that antiproliferative activity was not a result of overall hydrophobicity. Rather, SC-alpha alpha delta 9 decreased insulin-like growth factor-1 receptor tyrosine phosphorylation, receptor expression, mitogen-activated protein kinase activation and levels of the cyclin-dependent kinase Cdc2. Less toxic congeners only partially affected receptor expression, receptor tyrosine phosphorylation and Cdc2 levels. Thus SC-alpha alpha delta 9, which is structurally distinct from other known small molecules that decrease intracellular Cdc2 levels, has profound effects on intracellular signaling. Furthermore, SC-alpha alpha delta 9, but not vanadate or okadaic acid, selectively inhibited the growth of simian virus 40 large T antigen mouse embryonic fibroblasts compared to the parental cells. These results suggest that overexpression of Cdc2 and increased dependence on insulin-like growth factor-1 autocrine stimulation are responsible for the increased sensitivity of simian virus 40 large T antigen mouse embryonic fibroblasts to SC-alpha alpha delta 9. The SC-alpha alpha delta 9 pharmacophore could be a useful platform for the development of novel antisignaling agents.

0022-3565/98/2872-0806$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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