Medicinal chemistry

Milton Brown’s lab synthesizes compounds that could someday manage pain or treat prostate cancer.

By Linda J. Kobert
Brown.

Brown.
Photo by Jack Mellott.

Milton Brown works on a very small scale in his chemistry lab, but the compounds he and his team of scholars produce may someday have a very big impact on the medical world.

Brown, associate professor of chemistry at U.Va., is among a handful of physician scientists across the country who are working with medically significant proteins — many that are known to be important factors in pain or disease. Brown focuses on discovering small molecules that inhibit the proteins, in hopes of finding new compounds that someday may be used cure cancer or relieve pain without causing addiction.

Using computer models and computational methods, he searches for small molecules that fit like keys into receptor sites on the surface of these proteins. When he’s lucky — which he often is — the key that fits the lock opens the door to a new therapeutic effect that may eventually be developed into a pharmaceutical agent,

“Chemistry is a fundamental science,” Brown explained. “You can use the tools of chemistry to solve important problems in medicine. What I try to do is take a medical problem and back it down into something chemistry can solve.”

According to Brown, there is a shortage of unique, original therapeutic entities under investigation by the pharmaceutical industry. Despite the dozens of new drugs that hit the market every year, most are simply reformulations of known compounds that didn’t work or were less effective than desired.

“In the past, people in academic institutions have used chemistry to optimize yields, to do better chemistry to see if A will react with B,” Brown said. “But it’s like re-treading tires. What I’m interested in is finding novel drug-like molecules.”

Over the past year or so, Brown and the graduate students he calls his “team of committed young people who come from all over the country to work in my lab” have synthesized hundreds of completely new compounds that have never been reported or patented before.

Brown’s initial work in neurology focused on searching for entities that target ion channels related to seizure activity in the human brain. Some of these discoveries turned out to have relevance to pain management, targeting receptors in peripheral nerves rather than sites in the brain. Drugs created with these compounds have the potential for eliminating pain without central nervous system side effects such as drowsiness and euphoria.

More than 400 of these molecules have undergone a screening process to test their effect on human cells in the laboratory before being sent to the National Institute of Neurological Disease and Stroke at the National Institutes of Health. There, 30 were found to be clinically relevant, and Brown is currently focusing on four of these compounds that have been found to stop seizures in animal models and five that are relevant to pain management.

During that initial screening process, however, Brown noticed an interesting correlation. “It was found that the same channel we were studying in the brain for epilepsy was also found in prostate cancer cells,” he said. “And one morning I was eating Cheerios and it hit me: what is the incidence of prostate cancer in men who have been on these sodium channel blockers to treat their epilepsy?”

Anecdotally, some of his colleagues in urology had never treated prostate cancer in a patient with epilepsy. And when Brown did some investigating, he found that, even when he took age into account, these patients were 40 percent less likely to get prostate cancer than men in the general population.

Now Brown’s exploration has developed a parallel track in cancer research in which he has submitted more than 700 compounds to the National Cancer Institute. Testing on 60 human cancer lines has yielded more than 50 therapeutically relevant compounds. Among these are agents with promising effects on both colon and prostate cancer, as well as several types of leukemia.

Still, though he’s working at the cutting edge of medical science, Brown is modest about his personal impact on the future of clinical medicine. “All I’m hoping is that patients get relief from their diseases because of the things I do,” he quietly confides. “For someone to look me in my eyes and say, ‘Doc, I have no therapy,’ that just drives me completely to want to find new medicine.”

This article originally appeared in the May 6, 2005, issue of OscarNews.