1. Academic Validation
  2. Characterization of a Cdc42 protein inhibitor and its use as a molecular probe

Characterization of a Cdc42 protein inhibitor and its use as a molecular probe

  • J Biol Chem. 2013 Mar 22;288(12):8531-8543. doi: 10.1074/jbc.M112.435941.
Lin Hong 1 S Ray Kenney 2 Genevieve K Phillips 3 Denise Simpson 4 Chad E Schroeder 4 Julica Nöth 4 Elsa Romero 5 Scarlett Swanson 5 Anna Waller 1 J Jacob Strouse 1 Mark Carter 1 Alexandre Chigaev 5 Oleg Ursu 6 Tudor Oprea 6 Brian Hjelle 5 Jennifer E Golden 4 Jeffrey Aubé 7 Laurie G Hudson 8 Tione Buranda 5 Larry A Sklar 9 Angela Wandinger-Ness 10
Affiliations

Affiliations

  • 1 Department of Pathology, University of New Mexico, Albuquerque, New Mexico 87131; University of New Mexico (UNM) Center for Molecular Discovery, University of New Mexico, Albuquerque, New Mexico 87131.
  • 2 Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, New Mexico 87131.
  • 3 Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico 87131.
  • 4 University of Kansas Specialized Chemistry Center, Lawrence, Kansas 66047.
  • 5 Department of Pathology, University of New Mexico, Albuquerque, New Mexico 87131.
  • 6 University of New Mexico (UNM) Center for Molecular Discovery, University of New Mexico, Albuquerque, New Mexico 87131; Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico 87131; Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, New Mexico 87131.
  • 7 University of Kansas Specialized Chemistry Center, Lawrence, Kansas 66047; Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045.
  • 8 Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, New Mexico 87131; Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico 87131.
  • 9 Department of Pathology, University of New Mexico, Albuquerque, New Mexico 87131; University of New Mexico (UNM) Center for Molecular Discovery, University of New Mexico, Albuquerque, New Mexico 87131; Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico 87131. Electronic address: lsklar@salud.unm.edu.
  • 10 Department of Pathology, University of New Mexico, Albuquerque, New Mexico 87131; Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, New Mexico 87131. Electronic address: wness@unm.edu.
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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