A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions

Robert Kraft, Allon Kahn, José L. Medina-Franco, Mikayla L. Orlowski, Cayla Baynes, Fabian Loṕez-Vallejo, Jacobus J Barnard, Gerald M. Maggiora, Linda L Restifo

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)217-235
Number of pages19
JournalDMM Disease Models and Mechanisms
Volume6
Issue number1
DOIs
StatePublished - Jan 2013

Fingerprint

Bioassay
Biological Assay
Cognition
Neoplasm Metastasis
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Brain Diseases
Drug Discovery
Libraries
Neurons
Tumors
Assays
Brain
Screening
Pharmaceutical Preparations
Nootropic Agents
fascin
Neoplasms
Pseudopodia
Cell Shape
Genetic Models

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Neuroscience (miscellaneous)

Cite this

A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions. / Kraft, Robert; Kahn, Allon; Medina-Franco, José L.; Orlowski, Mikayla L.; Baynes, Cayla; Loṕez-Vallejo, Fabian; Barnard, Jacobus J; Maggiora, Gerald M.; Restifo, Linda L.

In: DMM Disease Models and Mechanisms, Vol. 6, No. 1, 01.2013, p. 217-235.

Research output: Contribution to journalArticle

Kraft, Robert ; Kahn, Allon ; Medina-Franco, José L. ; Orlowski, Mikayla L. ; Baynes, Cayla ; Loṕez-Vallejo, Fabian ; Barnard, Jacobus J ; Maggiora, Gerald M. ; Restifo, Linda L. / A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions. In: DMM Disease Models and Mechanisms. 2013 ; Vol. 6, No. 1. pp. 217-235.
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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.",
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