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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

Lin Hong, S Ray Kenney, Genevieve K Phillips, Denise Simpson, Chad E Schroeder, Julica Nöth, Elsa Romero, Scarlett Swanson, Anna Waller, J Jacob Strouse, Mark Carter, Alexandre Chigaev, Oleg Ursu, Tudor Oprea, etc.

J Biol Chem. 2013 Mar 22;288(12):8531-43.

PMID: 23382385

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1222513269	CID44216842		1222513-26-9	Price

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