Characterization of a Cdc42 Protein Inhibitor and Its Use as a Molecular Probe*

Autor: Jennifer E. Golden, J. Jacob Strouse, Lin Hong, Mark B. Carter, Anna Waller, Jeffrey Aubé, Oleg Ursu, Tione Buranda, Tudor I. Oprea, S. Ray Kenney, Julica Nöth, Genevieve K Phillips, Alexandre Chigaev, Brian Hjelle, Scarlett Swanson, Laurie G. Hudson, Angela Wandinger-Ness, Elsa Romero, Chad E. Schroeder, Denise S. Simpson, Larry A. Sklar
Jazyk: angličtina
Rok vydání: 2013
Předmět:
rac1 GTP-Binding Protein
Sin Nombre virus
Cytoskeleton organization
Proteinase inhibitor
Integrin
GTPase
CDC42
Integrin alpha4beta1
Biochemistry
Mice
0302 clinical medicine
Cell Movement
Cdc42
Pseudopodia
Enzyme Inhibitors
cdc42 GTP-Binding Protein
Cytoskeleton
Migration
0303 health sciences
Sulfonamides
Chemistry
Cell migration
3T3 Cells
Cell biology
3. Good health
Characterization (materials science)
Cdc42 GTP-Binding Protein
030220 oncology & carcinogenesis
Additions and Corrections
Signal transduction
biological phenomena
cell phenomena
and immunity
Molecular probe
Oligopeptides
Protein Binding
Cell Survival
Allosteric regulation
macromolecular substances
Biology
Antiviral Agents
03 medical and health sciences
Enzyme activator
Structure-Activity Relationship
Allosteric Regulation
Cell Line
Tumor
Animals
Humans
Molecular Biology
030304 developmental biology
Phenylurea Compounds
Cell Biology
Virus Internalization
Enzyme Activation
Molecular Probes
Biophysics
Pyrazoles
rhoA GTP-Binding Protein
Zdroj: The Journal of Biological Chemistry
ISSN: 1083-351X
0021-9258
Popis: Background: By integrating extracellular signals with actin cytoskeletal changes, Cdc42 plays important roles in cell physiology and has been implicated in human diseases. Results: A small molecule was found to selectively inhibit Cdc42 in biochemical and cellular assays. Conclusion: The identified compound is a highly Cdc42-selective inhibitor. Significance: The described first-in-class Cdc42 GTPase-selective inhibitor will have applications in drug discovery and fundamental research.
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.
Databáze: OpenAIRE
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