New program will help fill a drug-discovery void as pharmaceutical companies have largely abandoned natural products research

Jul 20 2005

The natural world has been medicine's most effective arsenal, providing life-saving antibiotics and our most potent anti-cancer drugs.

Now, with help from the National Cancer Institute (NCI), a consortium of University of Wisconsin-Madison scientists will embark on a five-year program of drug discovery by copying and improving nature's designs to develop new medicines to treat colon, breast, cervical and pancreatic cancer.

The new effort will involve faculty and staff scientists from the UW-Madison School of Pharmacy, the McArdle Laboratory for Cancer Research, and the UW Comprehensive Cancer Center.

"Natural products, especially those from microorganisms, have been a valuable source of new cancer drugs for many decades," says Ben Shen, a UW-Madison professor of pharmaceutical sciences and chemistry and the leader of the new National Cooperative Drug Discovery Group. Shen, working with Michael Hoffmann, Richard Hutchinson, Paul Lambert, Jon Thorson, Lynn Van Campen and other faculty and staff, will direct the $5.6 million multidisciplinary program to produce and test analogs of natural compounds that have potential as anti-cancer drugs.

The new program will help fill a drug-discovery void as pharmaceutical companies have largely abandoned natural products research. Identifying and synthesizing the very complex molecules that make up the biologically active compounds found in microbes, marine organisms and plants is a difficult process, Shen says. New drugs are needed desperately to replace and improve existing medicines, and to provide new avenues for treating cancers that resist treatment with current drugs.

"Some people believe the tank of natural products for drug use has run dry," says Shen. "But we don't think that's true at all."

He notes that 60-75 percent of drugs approved to treat infectious disease and cancer over the past 25 years are of natural origin.

New technologies, together with existing libraries of previously discovered natural compounds, will help the UW-Madison group identify and evaluate molecules that may have value in the fight against cancer. Techniques to genetically manipulate microbes and synthesize their biologically active products, plus novel mouse models of cancer and real-time tumor imaging methods, will underpin much of work in the new NCI-funded program.

In nature, biologically active compounds produced by plants and animals almost always have potential as medicines because they are effective at killing microbes or, in the context of runaway cell growth that is cancer, can inhibit the ability of cells to multiply and grow. But the molecules that make up those natural compounds are very complex and, frequently, generate problematic side effects.

The task of the new UW-Madison group will be to construct molecules that mimic natural anti-cancer agents, but that have been altered to reduce side effects and improve their efficacy.

"Mother Nature made these products, but not for us to use as a cancer drug," Shen explains. "The goal is to build molecules that maintain their biological activity but whose side effects have been limited."

With new compounds in hand, the group of researchers will first test them in drug screens in the lab and, for promising candidates, in new mouse models for the cancers the group is targeting.

"No one has been putting these compounds into the tests for use as cancer drugs in the way we plan," says Shen.

With traditional UW-Madison strengths in chemistry and biology, Shen believes the new program will flourish on campus. "We have a set of new technologies that will help us take some of these natural products to the next level of cancer drug discovery."

The ultimate goal, he says, is to establish a pipeline of natural-product analogs that will appeal to the pharmaceutical industry as ripe for development for the next generation of anti-cancer compounds.