Compound Blocks Cancer-Causing Protein

Their study is the first step towards developing a new type of anticancer agent that can block the Icmt protein from triggering unchecked growth, a key characteristic of cancer, according to Patrick Casey, Ph.D., the study's senior researcher and a Duke University pharmacologist and cancer biologist.

Duke University has filed a patent for cysmethynil and intends to process it through drug development testing protocols in animal models of cancer. "This is the first selective small molecule inhibitor of Icmt, a protein that has been shown to be an important player in keeping a cancer-causing gene, called Ras, turned on inside cells,” said Dr. Casey.

Ras is a normal genetic part of a cell, but mutations in the gene can cause it to become fixed in an activated phase, triggering uncontrolled cell growth. Mutations in Ras that permanently activate it have been discovered in half of all colon cancer and 90% of pancreatic cancers, and other cancers as well. Dr. Casey and coworkers have already found and developed another class of cancer drugs geared at inhibiting the processing pathway--the prenylation pathway--that regulates Ras. Dr. Casey and coworkers discovered several years ago how this pathway functions, which led to drug companies testing compounds that block another major piece in the pathway, a protein called farnesyltransferase. Inhibiting this protein blocks Ras' capacity to transmit growth-promoting signals inside cells. Several of these compounds have shown potential in treating lymphomas and leukemias, and are now under consideration for final approval by the U.S. Food and Drug Administration (FDA).

Dr. Casey and colleagues have now been assessing another major 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 last destination in the cell, from where it can transmit signals for uncontrolled growth. "Ras needs to be at the plasma membrane in order to function. 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,” Dr. Casey said. "We were looking for a small molecule that inhibited this enzyme specifically, without interfering with the normal regulation of the cell. What we found was a series of 30 structurally related molecules, and we selected the one with the highest potency--that is cysmethynil.”

Once the researchers had identified cysmethynil, they synthesized the molecule and validated its chemical structure. When the scientists tested the compound's ability to inhibit Ras function in living cells, they discovered that it blocked the ability of colon cancer cells to grow independently in soft agar, a typical test of the cancerous potential of cells. "The next step is to test cysmethynil in animal models. We don't know how the compound will be metabolized in living animals, but we are encouraged by our initial results,” stated Dr. Casey

The study was published in the March 22, 2005, issue of the journal Proceedings of the [U.S.] National Academy of Sciences.


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Duke Comprehensive Cancer Center