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dc.contributor.authorHong, Lin
dc.contributor.authorKenney, S. Ray
dc.contributor.authorPhillips, Genevieve K.
dc.contributor.authorSmipson, Denise
dc.contributor.authorSchroeder, Chad E.
dc.contributor.authorNöth, Julica
dc.contributor.authorRomero, Elsa
dc.contributor.authorSwanson, Scarlett
dc.contributor.authorWaller, Anna
dc.contributor.authorStrouse, J. Jacob
dc.contributor.authorCarter, Mark B.
dc.contributor.authorChigaev, Alexandre
dc.contributor.authorUrsu, Oleg
dc.contributor.authorOpera, Tudor
dc.contributor.authorHjulle, Brian
dc.contributor.authorGolden, Jennifer E.
dc.contributor.authorAubé, Jeffrey
dc.contributor.authorHudson, Laurie G.
dc.contributor.authorBuranda, Tione
dc.contributor.authorSklar, Larry A.
dc.contributor.authorWandinger-Ness, Angela
dc.identifier.citationHong, 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
dc.description.abstractCdc42 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.
dc.description.sponsorshipThis work was supported by National Science Foundation (NSF) Grant MCB0956027 and National Institutes of Health Grant R03 MH081231-01 from the Molecular Libraries Program (to A. W. N.); University of New Mexico Center for Molecular Discovery Molecular Libraries Probe Production Centers (UNMCMD MLPCN) National Institutes of Health Grants U54MH084690 and R01HL081062 (to L. A. S.); UNM National Center for Research Resources (NCRR) Grant 5P20RR016480 (to L. G. H.); National Institutes of Health Grant R21 CA170375-01 through the NCI (to A. W. N., L. G. H., and J. E. G.); National Institutes of Health Grants NS066429 and AI092130 (to T. B.); and University of Kansas Specialized Chemistry Center (KUSCC) MLPCN National Institutes of Health Grant U54HG005031 (to J. A.).
dc.publisherThe American Society for Biochemistry and Molecular Biology
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License .
dc.titleCharacterization of a Cdc42 Protein Inhibitor and Its Use as a Molecular Probe
kusw.kuauthorSimpson, Denise
kusw.kuauthorSchroeder, Chad E.
kusw.kuauthorNöth, Julica
kusw.kuauthorGolden, Jennifer E.
kusw.kuauthorAubé, Jeffrey
kusw.kudepartmentUniversity of Kansas Specialized Chemistry Center
kusw.kudepartmentDepartment of Medicinal Chemistry
kusw.oaversionScholarly/refereed, publisher version
kusw.oapolicyThis item meets KU Open Access policy criteria.

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License .
Except where otherwise noted, this item's license is described as: This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License .