Chemistry Professor Goes Broccoli One Better
In the Search for Cancer Immunotherapy Drug
Several years ago, research showed that brassinin, a chemical found in cruciferous vegetables like broccoli, has a mild anticancer effect. Later, researchers at the Lankenau Insititute for Medical Research proposed that brassinin and similar molecules work by inhibiting an enzyme that weakens immune response to tumors. The effect of the naturally occurring chemical, however, is too weak to make it useful as a drug, so the Lankenau scientists turned to Bryn Mawr Assistant Professor of Chemistry William Malachowski to help them create a more potent version of the compound.
Funded by a grant from the National Institutes of Health, the team has analyzed the brassinin molecule, making some important discoveries that will likely be critical as they synthesize the next generation of cancer immunotherapy drugs. Next week, Malachowski will present their findings, which were recently published in the Journal of Medicinal Chemistry, as the Second Annual Leroy B. Townsend Medicinal Chemistry Lecturer at the University of Michigan.
According to Malachowski, the idea for the potential new therapy has an origin that might seem unlikely at first glance: a hypothesis about fetal development.
"One of the oldest paradoxes in immunology," Malachowski explains, "is that a fetus, which has different DNA and a different antigenic profile than the mother, isn't attacked by the mother's immune system. In 1998, medical researchers in Georgia proposed the most convincing explanation to date of this phenomenon. They said that fetal tissue isn't rejected because the cells surrounding it produce an enzyme called indoleamine 2,3-dioxygenase (IDO). IDO degrades the amino acid tryptophan, an essential ingredient in the immune system's T-cells. With the T-cells out of the picture, the fetus can develop undisturbed."
There is a parallel paradox for cancer cells, Malachowski says: "Why doesn't the immune system attack cancer cells?" For some kinds of tumors, the answer seems to be the same: Cancer genes control the expression of IDO, which destroys T-cells.
The Lankenau researchers found that a combination of chemotherapy with an IDO suppressor significantly shrank tumors in mice.
"But the best IDO inhibitor that's currently in use is weak," Malachowski says. "You'd have to take a pill the size of a golf ball, and no one knows what kinds of side effects that much medication might have."
"We need an IDO inhibitor that is both potent and selective," he says. "This drug isn't like a hunting dog that sniffs its way to the target by finding molecules of scent it has dropped along the way. It has to have an affinity for the target so that it latches onto it when it finds it, but the drug will be distributed throughout the body, so it can't destroy everything it runs into along the way."
Malachowski and his colleagues have already synthesized an IDO inhibitor that is three times as powerful as the one currently in use, and they will continue the quest for still-more-powerful compounds. In their analysis, they broke the molecule into four components and studied the effect of each one. One of their most significant findings is that the "indole ring," the single element that is common to all IDO inhibitors that had been used before, is not an indispensable component - other chemical structures were effective substitutes. This "expands the range of structures that behave as IDO inhibitors," their paper says.
The team has been awarded two patents on the basis of their research and has contracted with New Links Genetics, an Iowa biotech company.
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