A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions
Robert Kraft1, Allon Kahn, José L Medina-Franco
1Department of Neuroscience, University of Arizona, Tucson, AZ 85721, USA.
Abstract:
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.
Insights
Researchers screened 1040 compounds to find fascin-pathway modulators. They identified 34 blockers for cancer metastasis and 48 enhancers for cognitive function, demonstrating a versatile drug discovery approach.
Area of Science:
- Molecular Biology
- Neuroscience
- Pharmacology
Background:
- The actin-bundling protein fascin is crucial for tumor invasion, metastasis, and cell migration.
- Fascin deficiency is implicated in developmental brain disorders.
- Developing assays for fascin function is key to identifying therapeutic modulators.
Purpose of the Study:
- To identify small molecules that modulate fascin pathways for potential therapeutic applications.
- To develop a bidirectional drug screen for both anti-metastasis and cognitive-enhancer activities.
- To explore the utility of Drosophila neuron cultures for drug discovery and neurotoxicity testing.
Main Methods:
- A cell-based assay using fascin-deficient Drosophila neurons with the 'filagree' phenotype was developed.
- A library of 1040 diverse compounds, including FDA-approved drugs, was screened for fascin-pathway modulators.
- Bidirectional screening identified compounds affecting fascin function and revealed drug-induced neurotoxicity.
Main Results:
- 34 fascin-pathway blockers with potential anti-metastasis activity were identified.
- 48 fascin-pathway enhancers with potential cognitive-enhancer activity were discovered.
- Statin-induced neurotoxicity was observed, exacerbated by fascin deficiency.
Conclusions:
- Primary neuron cultures in model organisms offer a valuable platform for early-stage drug discovery and developmental neurotoxicity assessment.
- Bidirectional screening for brain disorders and cancer is an efficient, multipurpose drug discovery strategy.
- The structural diversity of identified compounds suggests multiple molecular targets for fascin modulation.
