A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions.
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.
Department of Neuroscience, University of Arizona, Tucson, AZ 85721, USA.
Robert
R
Kraft
Allon
A
Kahn
José L
JL
Medina-Franco
Mikayla L
ML
Orlowski
Cayla
C
Baynes
Fabian
F
López-Vallejo
Kobus
K
Barnard
Gerald M
GM
Maggiora
Linda L
LL
Restifo
D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001681:Biological Assay / Q000379:methods; D001921:Brain / Q000254:growth & development; D001932:Brain Neoplasms / Q000188:drug therapy; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008959:Models, Neurological; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018697:Nootropic Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008840:Microfilament Proteins; D018697:Nootropic Agents; C020324:fascin