First-in-Class GTPase Inhibitor to Have Applications in Drug Discovery and Fundamental Research

A recent paper described the activity of a low molecular weight compound able to selectively inhibit the enzyme Cdc42 in biochemical and cellular assays that are expected to have applications in drug discovery and fundamental research.

Human Cdc42 is a small GTPase of the Rho-subfamily, which regulates signaling pathways that control diverse cellular functions including cell morphology, migration, endocytosis, and cell cycle progression. Overactive Cdc42 has been implicated in the pathology of cancers, immune diseases, and neuronal disorders. While Cdc42 inhibitors would be useful in probing molecular pathways and could have therapeutic potential, previous attempts to develop them have been unsuccessful, as the inhibitors have lacked selectivity and trended towards toxicity.

In the current study investigators at the University of New Mexico (Albuquerque, USA) succeeding in isolating a low molecular weight inhibitor of Cdc42 by high-throughput screening of hundreds of compounds.

They reported in the February 4, 2013, online edition of the Journal of Biological Chemistry that the compound, CID2950007, demonstrated excellent selectivity with no inhibition towards Rho and Rac from the same GTPase family. Biochemical characterization showed that the compound acted as a noncompetitive allosteric inhibitor. When tested in cellular assays, it inhibited Cdc42-related filopodia formation and cell migration.

CID2950007 was also used to clarify the involvement of Cdc42 in the internalization of Sin Nombre virus and the signaling pathway of integrin VLA-4.

“It is an important target in many diseases,” said senior author Dr. Angela Wandinger-Ness professor of pathology at the University of New Mexico. “Cancer is just one. But there were no compounds that target this GTPase. “There is a lot of enthusiasm for a compound like this—because there were not any. This is a first-in-class.”

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University of New Mexico