Identification and characterization of a small molecule inhibitor of formin-mediated actin assembly.
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.
Rizvi
Syed A
SA
Department of Chemistry, The University of Chicago, IL 60637, USA.
Neidt
Erin M
EM
Cui
Jiayue
J
Feiger
Zach
Z
Skau
Colleen T
CT
Gardel
Margaret L
ML
Kozmin
Sergey A
SA
Kovar
David R
DR
D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism; D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000187:drug effects; D000080865:Formins; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors*; D008856:Microscopy, Fluorescence; D041681:NIH 3T3 Cells; D017434:Protein Structure, Tertiary; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology; D012568:Schizosaccharomyces / Q000187:drug effects; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013871:Thiones / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D002352:Carrier Proteins; C491464:Diap1 protein, mouse; D000080865:Formins; D008840:Microfilament Proteins; D011744:Pyrimidinones; C547376:SMIFH2 compound; D054852:Small Molecule Libraries; D013871:Thiones; D014498:Uracil