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Newly Discovered Compound Blocks Known Cancer-Causing Protein

of the cell, but mutations in the gene can cause it to become stuck in an "on" position, promoting uncontrolled cell growth. Mutations in Ras that permanently activate it have been found in half of all colon cancer and 90 percent of pancreatic cancers, among other cancers.

Casey and his colleagues in Duke's Department of Pharmacology and Cancer Biology have already discovered and developed another class of cancer drugs aimed at inhibiting the processing pathway --the prenylation pathway ?that regulates Ras.

Several years ago, Casey's laboratory was one of a handful to unravel how the prenylation pathway works. This accomplishment led pharmaceutical companies to test compounds that block another key player in the pathway, a protein called farnesyltransferase. Blocking this protein inhibits Ras' ability to send growth-promoting signals inside cells. Several such compounds have shown promise in treating leukemias and lymphomas and are now under consideration for final approval by the U.S. Food and Drug Administration.

Since that time, Casey and his colleagues have been studying another key player in the pathway, the Icmt enzyme. Icmt adds a chemical tag called a "methyl group" to Ras. This methyl tag enables Ras to be directed to its final destination in the cell, from where it can send signals for unchecked growth.

"Ras needs to be at the plasma membrane in order to function," he said. "By preventing Icmt from adding a methyl group, we can effectively shut down Ras' ability to function, stopping it from sending signals for uncontrolled growth."

Initial experiments showed that knocking out the Icmt protein using genetic targeting also inhibited Ras, so the scientists decided to search for an effective and specific molecule that could inhibit Icmt function.

"We were looking for a small molecule that inhibited this enzyme specifically, without interfering with the normal regulation of the cell," said Casey. "What we found
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Source:DukeMedNews


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