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Characterization of a Cdc42 Protein Inhibitor and Its Use as a Molecular Probe
Hong, Lin ; Kenney, S. Ray ; Phillips, Genevieve K. ; Smipson, Denise ; Schroeder, Chad E. ; Nöth, Julica ; Romero, Elsa ; Swanson, Scarlett ; Waller, Anna ; Strouse, J. Jacob ... show 10 more
Hong, Lin
Kenney, S. Ray
Phillips, Genevieve K.
Smipson, Denise
Schroeder, Chad E.
Nöth, Julica
Romero, Elsa
Swanson, Scarlett
Waller, Anna
Strouse, J. Jacob
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Abstract
Cdc42 plays important roles in cytoskeleton organization, cell cycle progression, signal transduction, and vesicle trafficking. Overactive Cdc42 has been implicated in the pathology of cancers, immune diseases, and neuronal disorders. Therefore, Cdc42 inhibitors would be useful in probing molecular pathways and could have therapeutic potential. Previous inhibitors have lacked selectivity and trended toward toxicity. We report here the characterization of a Cdc42-selective guanine nucleotide binding lead inhibitor that was identified by high throughput screening. A second active analog was identified via structure-activity relationship studies. The compounds demonstrated excellent selectivity with no inhibition toward Rho and Rac in the same GTPase family. Biochemical characterization showed that the compounds act as noncompetitive allosteric inhibitors. When tested in cellular assays, the lead compound inhibited Cdc42-related filopodia formation and cell migration. The lead compound was also used to clarify the involvement of Cdc42 in the Sin Nombre virus internalization and the signaling pathway of integrin VLA-4. Together, these data present the characterization of a novel Cdc42-selective allosteric inhibitor and a related analog, the use of which will facilitate drug development targeting Cdc42-related diseases and molecular pathway studies that involve GTPases.
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Date
2013-02-04
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Publisher
The American Society for Biochemistry and Molecular Biology
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Keywords
Cdc42, Cytoskeleton, Gtpase, Intergin, Migration
Citation
Hong, Lin; Kenney, S. Ray; K. Phillips, Genevieve; Simpson, Denise; E. Schroeder, Chad; Nöth, Julica; Romero, Elsa; Swanson, Scarlett; Waller, Anna; Strouse, J. Jacob; Carter, Mark; Chigaev, Alexandre; Ursu, Oleg; Oprea, Tudor; Hjelle, Brian; E. Golden, Jennifer; Aubé, Jeffrey; Hudson, Laurie G.; Buranda, Tione; Sklar, Larry A.; & Wandinger-Ness, Angela; 2013 “Characterization of a Cdc42 Protein Inhibitor and Its Use as a Molecular Probe” J. Biol. Chem. 288:8531-8543 http://dx.doi.org/10.1074/jbc.M112.435941