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

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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This passage describes the identification and characterization of a new Cdc42-selective allosteric inhibitor, which could potentially be used for drug development and molecular pathway studies involving GTPases. The overactivity of Cdc42 has been implicated in various pathological conditions, and previous inhibitors lacked selectivity and were potentially toxic. Therefore, the identification of a selective inhibitor that does not inhibit other GTPases in the same family is significant. The lead compound and its analog were found to act as noncompetitive allosteric inhibitors and inhibited Cdc42-related filopodia formation and cell migration in cellular assays. The lead compound was also used to investigate the involvement of Cdc42 in the internalization of the Sin Nombre virus and the signaling pathway of integrin VLA-4. Overall, this study provides valuable insights into the development of selective inhibitors for Cdc42-related diseases and the molecular pathways involving GTPases.

 

Related Products

Cat.No. Product Name Information
S6000 CID44216842 CID44216842 (Cdc42-IN-1) is a potent Cdc42-selective guanine nucleotide binding lead inhibitor with EC50s of 1.0 μM and 1.2 μM for Cdc42WT and Cdc42Q61L mutant in GTP binding assay, respectively.

Related Targets

Rho