Disruption of insulin-like growth factor-1 signaling and down-regulation of cdc2 by SC-alphaalphadelta9, a novel small molecule antisignaling agent identified in a targeted array library.
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-decanoylami no butyric acid (SC-alphaalphadelta9), inhibited cell growth in the G0/G1 phase of the cell cycle. To investigate potential mechanisms for SC-alphaalphadelta9 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-alphaalphadelta9 and four library congeners demonstrated that antiproliferative activity was not a result of overall hydrophobicity. Rather, SC-alphaalphadelta9 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-alphaalphadelta9, which is structurally distinct from other known small molecules that decrease intracellular Cdc2 levels, has profound effects on intracellular signaling. Furthermore, SC-alphaalphadelta9, 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-alphaalphadelta9. The SC-alphaalphadelta9 pharmacophore could be a useful platform for the development of novel antisignaling agents.
Vogt
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A
Department of Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Rice
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RL
Settineri
C E
CE
Yokokawa
F
F
Yokokawa
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Wipf
P
P
Lazo
J S
JS
D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002472:Cell Transformation, Viral; D015536:Down-Regulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D019319:Okadaic Acid / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology; D020687:cdc25 Phosphatases
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D010080:Oxazoles; C115707:SC-alphaalphadelta9; D019319:Okadaic Acid; D014638:Vanadates; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D016203:CDC2 Protein Kinase; D010749:Phosphoprotein Phosphatases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D020687:cdc25 Phosphatases