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Identification of RAS-Mitogen-Activated Protein Kinase Signaling Pathway Modulators in an ERF1 Redistribution® Screen

BioImage A/S, Copenhagen, Denmark

Betina Kerstin Lundholt

BioImage A/S, Copenhagen, Denmark

Frosty Loechel

BioImage A/S, Copenhagen, Denmark

Hans-Christian Pedersen

BioImage A/S, Copenhagen, Denmark

Sara Petersen Bjørn

BioImage A/S, Copenhagen, Denmark

Viggo Linde

BioImage A/S, Copenhagen, Denmark

Christian Krogh-Jensen

BioImage A/S, Copenhagen, Denmark

Eva-Maria Damsgaard Nielsen

BioImage A/S, Copenhagen, Denmark

Morten Præstegaard

BioImage A/S, Copenhagen, Denmark

Søren Jensby Nielsen

BioImage A/S, Copenhagen, Denmark

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 (IC₅₀ =< 5 µM). 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.

Key Words: MAPK • Redistribution® • screen • high content

This version was published on June 1, 2006

Journal of Biomolecular Screening, Vol. 11, No. 4, 423-434 (2006)
DOI: 10.1177/1087057106287136


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