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Synthesized molecules studied as weapon to stop cell division in cancer cells

Blacksburg, Va., Aug. 23, 2004 -- An enzyme called Pin1, a gatekeeper of cell division, is present at high levels in a wide variety of cancer cells. Virginia Tech researchers who are designing small molecules to inhibit Pin1 are seeing promising results with a small U-shaped molecule.

Felicia Etzkorn, associate professor of chemistry, will report on her group's achievements in presentations at the 228th American Chemical Society (ACS) National Meeting in Philadelphia August 22-26.

Pin1 regulates the protein Cdc25, which initiates mitosis or cell division. Without Pin1, the cell enters programmed cell death -- which is good if it's a cancer cell.

"It makes sense to inhibit the Pin1 enzyme," said Etzkorn.

Protein shape determines biological function. Pin1 works by changing a peptide bond within Cdc25 from the trans shape (a flattened-Z shape) to the cis U-shape and back. This a simple change -- the swing of an arm one way or another to open or close the U results in a large conformation change in a protein.

The researchers synthesized cis and trans shaped inhibitors and introduced them into cancer cells. These inhibitors mimic part of the Cdc25 protein but do not bend to the will of Pin1. The research team discovered that cis inhibits the Pin1 enzyme's function 23 times better than trans. "This is very exciting because it tells us something fundamental about the mechanism.

The Etzkorn group tested the inhibitors in an ovarian cancer cell line. "That was the cell line that was available, but it should work for many cancers," Etzkorn said. "It would probably be particularly effective against breast cancer and prostate cancer. It seems to relate to secondary sexual characteristics."

However, a lot of work remains to be done to develop a drug, she cautions. "For instance, the inhibitor does not cross cell membranes. We can overcome that in the laboratory in order to study effectiveness, but have no
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Contact: Susan Trulove
strulove@vt.edu
540-231-5646
Virginia Tech
23-Aug-2004


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