Identification of RAS-mitogen-activated protein kinase signaling pathway modulators in an ERF1 redistribution screen
| Autor: | Charlotta Grånäs, Morten Praestegaard, Viggo Linde, Søren Jensby Nielsen, Frosty Loechel, Betina Kerstin Lundholt, Sara Petersen Bjørn, Eva-Maria Damsgaard Nielsen, Hans-Christian Pedersen, Christian Krogh-Jensen |
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| Rok vydání: | 2006 |
| Předmět: |
MAPK/ERK pathway
MAP Kinase Signaling System Focus area Drug Evaluation Preclinical Biology In Vitro Techniques Transfection Biochemistry Analytical Chemistry Cell Line Cell Line Tumor Cricetinae Animals Humans ASK1 c-Raf Phosphorylation RNA Small Interfering Protein kinase A Protein kinase B Cell Proliferation Molecular Structure Cell biology DNA-Binding Proteins Repressor Proteins Mitogen-activated protein kinase biology.protein Molecular Medicine Signal transduction Biotechnology Transcription Factors |
| Zdroj: | Journal of biomolecular screening. 11(4) |
| ISSN: | 1087-0571 |
| Popis: | The RAS-mitogen-activated protein kinase (MAPK) signaling pathway has a central role in regulating the proliferation and survival of both normal and tumor cells. This pathway has been 1 focus area for the development of anticancer drugs, resulting in several compounds, primarily kinase inhibitors, in clinical testing. The authors have undertaken a cell-based, high-throughput screen using a novel ERF1 Redistribution assay to identify compounds that modulate the signaling pathway. The hit compounds were subsequently tested for activity in a functional cell proliferation assay designed to selectively detect compounds inhibiting the proliferation of MAPK pathway-dependent cancer cells. The authors report the identification of 2 cell membrane-permeable compounds that exhibit activity in the ERF1 Redistribution assay and selectively inhibit proliferation of MAPK pathway-dependent malignant melanoma cells at similar potencies (IC(50)=5 microM). These compounds have drug-like structures and are negative in RAF, MEK, and ERK in vitro kinase assays. Drugs belonging to these compound classes may prove useful for treating cancers caused by excessive MAPK pathway signaling. The results also show that cell-based, high-content Redistribution screens can detect compounds with different modes of action and reveal novel targets in a pathway known to be disease relevant. |
| Databáze: | OpenAIRE |
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