title: Small Molecules Revealed in a Screen Targeting Epithelial Scattering Are Inhibitors of Microtubule Polymerization.
abstract: Stimulation of cultured epithelial cells with scatter factor/hepatocyte growth factor (HGF) results in the detachment of cell-cell junctions and initiation of cell migration. Instead of coordinating collective cell behavior within a tissue, cells become solitary and have few cell-cell interactions. Since epithelial scattering is recapitulated in cancer progression and since HGF signaling drives cancer metastasis in many cases, inhibitors of HGF signaling have been proposed to act as anticancer agents. We previously sought to better understand critical components required for HGF-induced epithelial scattering by performing a forward chemical genetics screen, which resulted in the identification of compounds with no previously reported biological activity that we report here. In efforts to determine the mechanism of these compounds, we find that many compounds have broad antiproliferative effects on cancer cell lines by arrest of cell division in G2/M with minimal induction of apoptosis. This effect is reminiscent of microtubule-targeting agents, and we find that several of these scaffolds directly inhibit microtubule polymerization. Compounds are assessed for their toxicity and pharmacokinetics in vivo. The identification of novel small-molecule inhibitors of microtubule polymerization highlights the role of the microtubule cytoskeleton in HGF-induced epithelial scattering.
authors.affiliation: Brigham Young University, Provo, UT, USA.
authors.forename: Taylor H
authors.initials: TH
authors.lastname: Hoj
authors.affiliation: Brigham Young University, Provo, UT, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Robinson
authors.affiliation: Baylor College of Medicine, Houston, TX, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Burton
authors.affiliation: Brigham Young University, Provo, UT, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Densley-Ure
authors.affiliation: Brigham Young University, Provo, UT, USA.
authors.forename: Tyler V
authors.initials: TV
authors.lastname: Olson
authors.affiliation: Brigham Young University, Provo, UT, USA.
authors.forename: Logan K
authors.initials: LK
authors.lastname: Williams
authors.affiliation: Samford University, Birmingham, AL, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Coward
authors.affiliation: Samford University, Birmingham, AL, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Gorman
authors.affiliation: Brigham Young University, Provo, UT, USA marchansen@byu.edu.
authors.forename: Marc D H
authors.initials: MD
authors.lastname: Hansen
mesh_terms: D000970:Antineoplastic Agents / Q000302:isolation & purification* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D058105:Polymerization / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C066855:HGF protein, human; D054852:Small Molecule Libraries; D017228:Hepatocyte Growth Factor
keywords: cell-based assays; microtubule; oncology; phenotypic drug discovery