Pharmaceutical Sciences Faculty Publications

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

Document Type

Article

Publication Date

3-22-2013

Journal Title

The Journal of Biological Chemistry

ISSN

1083-351X

Volume

288

Issue

12

First Page

8531

Last Page

8543

DOI

http://dx.doi.org/10.1074/jbc.m112.435941

PubMed ID

23382385

PubMed Central® ID

PMC3605667

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.

Keywords

Cdc42, cytoskeleton, GTPase, integrin, migration

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