Development of a novel small molecule that mimics the action of the key apoptosis-promoting protein Smac could lead to more effective therapies against cancer that have fewer side effects, according to an article in the September 3rd issue of Science.

A member of the American research team, Dr. Xiaodong Wang, discovered Smac in 2000. He said, “Every cell in our body has a self-destruction apparatus that becomes activated when a cell needs to be terminated. The Smac protein is one component of this normal cell-suicide process, called apoptosis.”

In healthy cells, Smac is sequestered within mitochondria until the mitochondrion receives signals to release it. Smac then interacts with other molecules called inhibitor-of-apoptosis proteins (IAPs), which, if not countered by Smac, will keep the cell alive and growing.

In cancer cells, two parts of the process often go wrong: IAPs tend to be overexpressed and the signals that tell mitochondria to release Smac are often defective. The fact that the Smac mimic can enter the cytoplasm of cells unhindered is an important step in developing new cancer therapies, said Dr. Patrick Harran, a coauthor of the study.

The compound, which so far has only been tested on cells in vitro, does not appear to harm normal cells, just cancer cells, said Dr. Wang. He said other research groups as well as pharmaceutical companies have been trying to develop a small-molecule Smac mimic.

The Smac mimic was actually discovered by accident. Based on information about how Smac binds to IAPs, the researchers designed molecules they thought would mimic this interaction. They prepared and screened hundreds of candidates. Smac is a large molecule and is also a dimer of two identical halves. Dr. Harran, an organic chemist, said their original candidate molecules were monomers.

“While working with a particular monomer, we performed a chemical reaction that caused it to dimerize,” Dr. Harran said. “Even though we didn’t realize this had happened at first, the dimer’s activity as a Smac mimic was off the charts relative to everything else in our collection.”

The monomer also showed activity, but it was not nearly as effective at facilitating apoptosis as the dimer. One of the advantages of the Smac mimic, Dr. Wang said, is that if cancer treatments were to be developed from it, dosages would likely be small.

“There is reason to believe that this could be one of the first examples of a catalytic drug,” Dr. Harran said. “You may not need one Smac-mimic molecule for each IAP in a cell. You likely need fewer of our Smac mimics than IAPs to neutralize IAP effects, because once the cell death program gets started, it generates more Smac-like activity as it proceeds.”

Dr. Wang said, “If this turns out to be true, it’s remarkable, because then you would only need a tiny amount to have a dramatic impact.” The next step in the research is to test the compound in animals. “If it does well, hopefully it will someday find its way to people,” he said. “That’s the ultimate goal.”