A Lab with a View:
Tom Bannister Looks for Potential New Drugs
By Eric Sauter
Tom Bannister, an associate director of medicinal chemistry at Scripps Florida, was born in Seymour, Indiana, made famous by singer-songwriter John Mellencamp in the song "Small Town." He grew up nearby on a dairy farm with his two bothers and a sister, who all helped milk about 50 of the familiar black-and-white Holstein cows.
"We did a morning milking before school, and then another milking when we got home from school," he said. "I remember driving the tractors and bailing hay as a farm kid. I still miss the fresh air and open spaces. When my family and I came to Florida, we found a place west of I-95 where there are bigger lots, with neighbors that even have horses and other animals. I didn't want to live in a townhouse."
Despite the attractions of the Midwest, Bannister moved to follow his interest in science, at first for jobs in the pharmaceutical industry, and then, in 2006, to join the Scripps Florida faculty.
"When I go back [to the Midwest], I'm a little like a fish out of water, things are a bit slow-moving," he said. "But I'm still something of a Midwesterner at heart."
From Holsteins to Palm Trees
Bannister attended Wabash College, a small Indiana liberal arts college for men, but at first wasn't quite sure what he was going to do there. He had won a scholarship based on a history exam, but preferred math and science.
"I thought I would be a math or physics major, but freshman year I decided I liked chemistry best," he said. "History was never in my plans as a major, though I still have interests in the topic—my wife and three kids have to wrestle away the remote control to switch off the History Channel."
Bannister went to Yale for his master's degree and then to Indiana University for his Ph.D. in organic chemistry. He decided against doing postdoctoral work after he landed an interview at Marion Merrell Dow Pharmaceuticals in Cincinnati, Ohio.
"I went for an interview, hit it off with the people I talked to, and noticed that they had several good scientists working there—like Albert Carr, the inventor of the antihistamine Allegra—and I spent a lot of time talking to them about chemistry and I decided to get into drug discovery research as soon as I could," he said.
Bannister was involved in early-discovery-stage research at Marion Merrell Dow, spending time on compounds for asthma and cardiovascular diseases. After four years, he moved to Sepracor in Massachusetts.
One of the unfortunate aspects of the Sepracor job was that the labs, though well equipped, were windowless. Five years later, a former Yale classmate was setting up a chemistry research unit for a small company in Cambridge, Massachusetts, so Bannister joined him to become a chemistry group leader. When the company was acquired and then closed by a larger Japanese firm, Bannister began exploring his options.
"I was thinking about what to do and so I called Bill Roush—my advisor back in Indiana," he said. "I wasn't really thinking about Scripps as an option at that point, I just sought his advice in general. He called back and filled me in on the medicinal chemistry program being built at Scripps Florida, [where Roush is professor and associate dean of the Kellogg School of Science and Technology] and got me to visit."
That was 2006. Bannister stuck around. At Scripps Florida, his lab does have windows. Outside you can see at least 50 palm trees, though no Holsteins.
In industry and also at Scripps Florida, Bannister's practical approach to drug discovery is reflected by the time he has spent accumulating patents for compounds to treat various diseases, everything from chronic pain, drug-resistant infections, depression, and blood clotting disorders, to his current work with kinase inhibitors. The goal to aggressively pursue patents—he has had nine published patents or patent applications emerging in just the past two years—is the mark of a product-focused approach not usually seen in academics.
"In drug discovery research, it's vitally important to get a good patent position," he said. "After that is taken care of, you can consider journal publications. To some extent, it's frustrating for scientists, since the patenting process can be very slow, but you get used to it. The publishing can wait until after the patents are issued. That's how it works in the biotech and pharmaceutical industry, and since members of these industries are the future collaborators for us in the Translational Research Institute, we have to have the same goals in mind."
His goal for his research at Scripps Florida is to find something that will one day become a drug.
Bannister notes that the focus in the Translational Research Institute at Scripps Florida is rapidly finding the best molecules for a given protein target, optimizing their properties with an eye toward using them in fighting a disease.
"Scripps Florida is pretty rare in taking this broad approach in a non-profit research environment, dedicated to meeting the tough challenge of discovering drug development candidates," he said. "In a pure academic setting, you might develop an x-ray crystal structure and then make the best inhibitor you could. You could then perhaps call your work done, and publish it quickly. Here, you might make the best inhibitor based upon the biochemical screens, but then go further, identifying reasons why a compound won't work so you can keep looking for something that will. It's a big mind shift.
The interdisciplinary approach at Scripps Florida maximizes the opportunity to recognize—and manage—all the many areas of potential failure inherent to the drug discovery process.
"In the early stages of research, you don't think of it in terms of compounds, you think of mechanisms. Then you hope to make multiple compounds that act by the same mechanism. The idea isn't to make one compound to test the idea; it's to make ten compounds [so that at least one might work]. There is just so much unpredictability to the process, so you hedge your bets. It's a funnel design—as smart as you think you are, you still have to put a lot of compounds in at the top to get something worthwhile to come out at the bottom."
ROCK in the USA
Bannister's main candidate for the drug discovery funnel these days is designing inhibitors of Rho-kinase (ROCK). ROCK is involved in regulating smooth-muscle contraction, cell movement, and cell adhesion. ROCK inhibitors have potential for treating everything from cardiovascular diseases to spinal cord injury, cancer, and glaucoma. A ROCK inhibitor, fasudil, is marketed in Japan for cerebral vasospasm, and many ROCK inhibitors are progressing toward clinical trials for other diseases. Human clinical data and animal experiments have shown efficacy of ROCK inhibitors in treating cardiovascular diseases, cancer, and glaucoma. The many functions of ROCK make it a good target for drug discovery, but at the same time its many roles raise concerns about how to establish a therapy selective for treating just one condition.
"Right now my chemistry group is working closely with Yangbo Feng's chemistry group [at Scripps Florida] and with an entire team of biologists and pharmacologists headed by Phil LoGrasso [of Scripps Florida] as well as a collaborator at Duke University," he said. "We think we can produce a new and more effective drug for treating glaucoma. Glaucoma is a particularly difficult disease to treat and current treatments just aren't adequate. Many of the drugs in clinical trials now, if they work at all, might offer only a slight improvement over existing medications that also have issues."
Glaucoma, a form of progressive retinal neurodegeneration, affects more than 70 million people worldwide and an estimated half of those afflicted are yet undiagnosed. About 2.5 million Americans have chronic open-angle glaucoma, the most common form in the United States, which is associated with long-term elevation in intraocular pressure. ROCK inhibitors have been shown to decrease intraocular pressure in a human clinical trial.
The Bannister and Feng groups have been looking for proprietary ROCK inhibitors that address the limitations of other glaucoma treatments and also are superior to other known ROCK inhibitors, especially in their selectivity and their potency in cell-based assays. The design of the lead compounds is based upon a combination of a critical evaluation of the structures and properties of known ROCK inhibitors coupled with new screening hits that emerged from a high-throughput screening campaign at Scripps Florida. The result has been a number of leads designed to have remarkably high potency.
"We are taking a soft-drug approach, targeting compounds that are optimized for local delivery to the eye, having strong effects there, and yet if and when they leave the eye, they are broken down and are cleared from the system quickly," he said. "If they were not cleared and if high concentrations of ROCK inhibitors were to spread all over the body, it would raise the potential for side effects like lowered blood pressure. "
The ROCK inhibitors Bannister, Feng, and colleagues are advancing act by a different pathway than currently available anti-glaucoma drugs, offering what he says is a significant advantage in their ability to address elevated intraocular pressure—the primary cause of glaucoma—and subsequently to protect the eye from the rapid deterioration often seen in people suffering from the disease.
"Our best compounds are highly potent in cells, and early data suggest that they are potent in animals, too," he said. "Glaucoma drugs generally must be used in high doses and very frequently, resulting in side effects like irritation, changes in eye color, and temporarily blurred vision. With more potent and long-acting compounds, we hope to avoid those side effects. We could use far less and yet still get a maximum effect. Our best compounds are also "clean" in that they bind to very few other kinases, so we feel the chances for other safety problems are lower. We have confidence that out compounds lower intraocular pressure the way we thought they would."
The side effects of current glaucoma treatments can be more than just an annoyance. Some epidemiological studies have suggested one glaucoma drug raises patients' risk of a heart attack.
"If you have a compound with far fewer and less serious side effects—and the goal is always no side effects at all—you might be able to convince people to start taking it when their first symptoms show. That is exactly what a great many glaucoma patients don't do and what we're trying to accomplish."
In another potential endeavor, Bannister has submitted a grant application to study the ability of a different type of ROCK inhibitor to halt cancer cell metastasis.
Bannister is also working with Scripps Florida colleague Patricia McDonald and co-workers to develop a potential new treatment for Type 2 diabetes. A third collaboration is with Scripps Florida's Claes Wahlestedt and co-workers, seeking new drugs to treat alcohol addiction; they recently submitted a grant to fund a pilot study after finding some initial promising compounds.
"What I like most about these collaborations is that we are always facing new experimental obstacles and then we see if there's a chemistry solution for it," Bannister said. "If we block the enzyme but the effect lasts only a few hours, how do we solve that? Is there a connection to the chemical structure, how can we make sense of it, what do we try, and what surprises will we get? You really have to keep an open mind about designing experiments. When you find a chemistry solution for a problem, it no longer seems like obstacle; it's more like an opportunity to move forward to the next hurdle. We hope we run out of hurdles some day. That might mean we have something really useful—something I'd want my friends or family to take if they are ever afflicted with a disease like glaucoma."
Send comments to: mikaono[at]scripps.edu
Currently, Tom Bannister is focusing his research on inhibitors of Rho-kinase (ROCK), which have potential for treating glaucoma, cancer, and other diseases. Photo by Eric Sauter.
"The idea isn't to make one compound to test the idea; it's to make ten compounds [so that at least one might work]."