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Fox Chase researchers discover a method for clamping down on a cancer-promoting enzyme
Date:4/18/2008

There are many pathways that allow an errant gene to turn a cell cancerous, and a number of these pathways go through a single enzyme called the p21-activated kinase 1, or PAK1.

Researchers at Fox Chase Cancer Center have now identified a molecule capable of shutting down PAK1 before the enzyme becomes active. Previous studies have linked PAK1 activity with breast cancer and have shown the enzyme is important in pathways involving the ras oncogene, which is thought to cause up to 30 percent of all cancers.

In the April 24 issue of the journal Chemistry & Biology, the researchers detail how the molecule, called IPA-3, was found from a screen of nearly 33,000 small molecules, and could serve as a basis for future breast cancer or cancer therapeutics. Cell-based studies using IPA-3 confirm that the molecule is capable of blocking signaling by the PAK1 pathway.

Previous work suggested that hyperactive signaling by PAK1 can contribute to the growth of tumors, but the trick is how to selectively block PAK1 without damaging similar enzymes that are crucial for healthy cellular function, said lead investigator Jeffrey R. Peterson, Ph.D, an associate member of Fox Chase. IPA-3 represents a proof-of-principle, illustrating a new and highly selective approach to targeting PAK1.

PAK1, like all kinases, is an enzyme that regulates other proteins by attaching an energetic molecule to them in a process known as phosphorylation. The active site where the phosphorylation reaction occurs is an attractive target for drug development, since blocking the active site would deactivate the enzyme. Unfortunately, the active site of PAK1 shares a molecular architecture similar to that found in many other kinase enzymes. Previous attempts to inhibit the PAK1 active site chemically have also resulted in inhibiting PAK1-related enzymes, with toxic consequences.

Instead of finding another molecule that binds to the active site, Peterson an
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Contact: Greg Lester
gregory.lester@fccc.edu
215-728-2753
Fox Chase Cancer Center
Source:Eurekalert

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