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

• Published in: Chemistry & biology Vol. 16; no. 11; pp. 1158 - 1168
• Main Authors: Rizvi, Syed A., Neidt, Erin M., Cui, Jiayue, Feiger, Zach, Skau, Colleen T., Gardel, Margaret L., Kozmin, Sergey A., Kovar, David R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 25.11.2009
• Subjects: 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; 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
• ISSN: 1074-5521; 1879-1301
• DOI: 10.1016/j.chembiol.2009.10.006

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 ∼5 to 15 μM. 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.