Identification and Characterization of a Small Molecule Inhibitor of Formin-Mediated Actin Assembly

Chem Biol. 2009 Nov 25;16(11):1158-68. doi: 10.1016/j.chembiol.2009.10.006.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / drug effects*
  • Actin Cytoskeleton / metabolism
  • Actin-Related Protein 2-3 Complex / metabolism
  • Actins / chemistry
  • Actins / metabolism*
  • Animals
  • Carrier Proteins / antagonists & inhibitors*
  • Cell Line, Tumor
  • Cytoskeleton / drug effects
  • Formins
  • Humans
  • Mice
  • Microfilament Proteins / antagonists & inhibitors*
  • Microscopy, Fluorescence
  • NIH 3T3 Cells
  • Protein Structure, Tertiary
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology
  • Schizosaccharomyces / drug effects
  • Small Molecule Libraries
  • Structure-Activity Relationship
  • Thiones / chemistry
  • Thiones / pharmacology*
  • Thiones / toxicity
  • Uracil / analogs & derivatives*
  • Uracil / chemistry
  • Uracil / pharmacology
  • Uracil / toxicity

Substances

  • Actin-Related Protein 2-3 Complex
  • Actins
  • Carrier Proteins
  • Diap1 protein, mouse
  • Formins
  • Microfilament Proteins
  • Pyrimidinones
  • SMIFH2 compound
  • Small Molecule Libraries
  • Thiones
  • Uracil