PT - JOURNAL ARTICLE AU - Andreas Vogt AU - Robert L. Rice AU - Catherine E. Settineri AU - Fumiaki Yokokawa AU - Shiho Yokokawa AU - Peter Wipf AU - John S. Lazo TI - Disruption of Insulin-Like Growth Factor-1 Signaling and Down-Regulation of Cdc2 by SC-ααδ9, a Novel Small Molecule Antisignaling Agent Identified in a Targeted Array Library DP - 1998 Nov 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 806--813 VI - 287 IP - 2 4099 - http://jpet.aspetjournals.org/content/287/2/806.short 4100 - http://jpet.aspetjournals.org/content/287/2/806.full SO - J Pharmacol Exp Ther1998 Nov 01; 287 AB - 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-ααδ9), inhibited cell growth in the G0/G1 phase of the cell cycle. To investigate potential mechanisms for SC-ααδ9 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-ααδ9 and four library congeners demonstrated that antiproliferative activity was not a result of overall hydrophobicity. Rather, SC-ααδ9 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-ααδ9, which is structurally distinct from other known small molecules that decrease intracellular Cdc2 levels, has profound effects on intracellular signaling. Furthermore, SC-ααδ9, 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-ααδ9. The SC-ααδ9 pharmacophore could be a useful platform for the development of novel antisignaling agents. The American Society for Pharmacology and Experimental Therapeutics