Document Detail

Identification and characterization of a small molecule inhibitor of formin-mediated actin assembly.
MedLine Citation:
PMID:  19942139     Owner:  NLM     Status:  MEDLINE    
Formins stimulate actin filament assembly for fundamental cellular processes including division, adhesion, establishing polarity, and motility. A formin inhibitor would be useful because most cells express multiple formins whose functions are not known and because metastatic tumor formation depends on the deregulation of formin-dependent processes. We identified a general small molecule inhibitor of formin homology 2 domains (SMIFH2) by screening compounds for the ability to prevent formin-mediated actin assembly in vitro. SMIFH2 targets formins from evolutionarily diverse organisms including yeast, nematode worm, and mice, with a half-maximal inhibitor concentration of approximately 5 to 15 microM. SMIFH2 prevents both formin nucleation and processive barbed end elongation and decreases formin's affinity for the barbed end. Furthermore, low micromolar concentrations of SMIFH2 disrupt formin-dependent, but not Arp2/3 complex-dependent, actin cytoskeletal structures in fission yeast and mammalian NIH 3T3 fibroblasts.
Syed A Rizvi; Erin M Neidt; Jiayue Cui; Zach Feiger; Colleen T Skau; Margaret L Gardel; Sergey A Kozmin; David R Kovar
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chemistry & biology     Volume:  16     ISSN:  1879-1301     ISO Abbreviation:  Chem. Biol.     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-11-27     Completed Date:  2010-03-02     Revised Date:  2014-11-12    
Medline Journal Info:
Nlm Unique ID:  9500160     Medline TA:  Chem Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1158-68     Citation Subset:  IM    
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MeSH Terms
Actin Cytoskeleton / drug effects*,  metabolism
Actin-Related Protein 2-3 Complex / metabolism
Actins / chemistry,  metabolism*
Carrier Proteins / antagonists & inhibitors*
Cell Line, Tumor
Cytoskeleton / drug effects
Microfilament Proteins / antagonists & inhibitors*
Microscopy, Fluorescence
NIH 3T3 Cells
Protein Structure, Tertiary
Pyrimidinones / chemistry,  pharmacology
Schizosaccharomyces / drug effects
Small Molecule Libraries
Structure-Activity Relationship
Thiones / chemistry,  pharmacology*,  toxicity
Uracil / analogs & derivatives*,  chemistry,  pharmacology,  toxicity
Grant Support
5DP1OD003354/OD/NIH HHS; DP1 OD003354/OD/NIH HHS; DP1 OD003354-01/OD/NIH HHS; DP1 OD003354-02/OD/NIH HHS; DP1 OD003354-03/OD/NIH HHS; R01 GM079265/GM/NIGMS NIH HHS; R01 GM079265-03/GM/NIGMS NIH HHS; R01GM079265/GM/NIGMS NIH HHS
Reg. No./Substance:
0/Actin-Related Protein 2-3 Complex; 0/Actins; 0/Carrier Proteins; 0/Diap1 protein, mouse; 0/Microfilament Proteins; 0/Pyrimidinones; 0/SMIFH2 compound; 0/Small Molecule Libraries; 0/Thiones; 56HH86ZVCT/Uracil
Comment In:
Chem Biol. 2009 Nov 25;16(11):1125-6   [PMID:  19942132 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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