A first-of-its-kind, proof-of-concept drug screen with implications for two unmet medical needs. / The actin-bundling protein fascin is a key mediator of tumor invasion and metastasis and its activity drives filopodia formation, cell-shape changes and cell migration. Small-molecule inhibitors of fascin block tumor metastasis in animal models. Conversely, fascin deficiency might underlie the pathogenesis of some developmental brain disorders. To identify fascin-pathway modulators we devised a cell-based assay for fascin function and used it in a bidirectional drug screen. The screen utilized cultured fascin-deficient mutant Drosophila neurons, whose neurite arbors manifest the 'filagree' phenotype. Taking a repurposing approach, we screened a library of 1040 known compounds, many of them FDA-approved drugs, for filagree modifiers. Based on scaffold distribution, molecular-fingerprint similarities, and chemical-space distribution, this library has high structural diversity, supporting its utility as a screening tool. We identified 34 fascin-pathway blockers (with potential anti-metastasis activity) and 48 fascin-pathway enhancers (with potential cognitive-enhancer activity). The structural diversity of the active compounds suggests multiple molecular targets. Comparisons of active and inactive compounds provided preliminary structure-activity relationship information. The screen also revealed diverse neurotoxic effects of other drugs, notably the 'beads-on-a-string' defect, which is induced solely by statins. Statin-induced neurotoxicity is enhanced by fascin deficiency. In summary, we provide evidence that primary neuron culture using a genetic model organism can be valuable for early-stage drug discovery and developmental neurotoxicity testing. Furthermore, we propose that, given an appropriate assay for target-pathway function, bidirectional screening for brain-development disorders and invasive cancers represents an efficient, multipurpose strategy for drug discovery.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/605272 |
| Date | 01 1900 |
| Creators | Kraft, Robert, Kahn, Allon, Medina-Franco, José L., Orlowski, Mikayla L., Baynes, Cayla, López-Vallejo, Fabian, Barnard, Kobus, Maggiora, Gerald M., Restifo, Linda L. |
| Contributors | Department of Neuroscience, University of Arizona, Tucson, AZ, Torrey Pines Institute for Molecular Studies, Port St Lucie, FL, Department of Computer Science, University of Arizona, Tucson, AZ, BIO5 Interdisciplinary Research Institute, University of Arizona, Tucson, AZ, Translational Genomics Research Institute, Phoenix, AZ, Department of Pharmacology and Toxicology, Arizona Health Sciences Center, Tucson, AZ, Departments of Neurology and Cellular & Molecular Medicine, Arizona Health Sciences Center, Tucson, AZ, Center for Insect Science, Arizona Research Laboratories, University of Arizona, Tucson, AZ |
| Publisher | The Company of Biologists |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | Article |
| Rights | Archived with thanks to Disease models & mechanisms |
| Relation | http://dmm.biologists.org/content/6/1/217.long |
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