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Pitt has a new breed of multidisciplinary scientists. Housed in the Combinatorial Chemistry Center, they are changing the rules when it comes to drug discovery. Their work promises to provide an important boost for researchers worldwide.

Winning Combination

Written by Kris B. Mamula

Open on one counter is a hardbound notebook, its pages crammed with handwritten notes in blue ink. On an opposing counter are two glass containers, each about the size of a baseball. The researcher darts between the counters, back and forth, back and forth, as though propelled by gusts of air. Her lips move but make no sound, she traces lines in the notebook with her forefinger, checkmarking some lines with a pen as though ticking off steps in a cake recipe. The glass containers are each half-filled with clear fluid. “I don’t know how this can be interesting,” she says, smiling and using her forearm to brush away a wisp of brown hair that has fallen across her goggles.

But it is.

She shrugs and looks away suddenly. “We can talk after I set this up,” she says. An imposing boom box on the top of the refrigerator is mute. She carefully draws fluid from a brown medicine-like bottle into a tiny orange syringe. She pushes the needle through the rubber cap on one of the glass containers. Slowly, slowly, slowly, she teases the syringe plunger, drop by drop, squeezing the liquid into one of the glass balls. She leans heavily into the counter, steadying herself, transfixed, her eyes never moving from the syringe. Inside the container, the liquid is turning Post-it Notes yellow. It’s as though the lab, the entire Chevron Science Building, and the rest of the world has somehow fallen away around her, leaving only the syringe and glass bulb in her universe.

What she’s doing is interesting because it was a day much like this one three months earlier when the same determination, the same obsession, yielded some surprising results. “Something’s wrong here,” was her first reaction that day, disbelieving her good fortune. She ran the test again. Maybe something wasn’t wrong after all. “This is something really good,” she thought.

Jelena Janjic (pronounced “YELL-en-a JAN-sic”) was volunteering as a research assistant at the University of Pittsburgh Cancer Institute three years ago when she began thinking about enrolling at Pitt to study medicinal chemistry and get a PhD. She had been a pharmacist in her native Serbia for a year before following her husband, Bratislav, to Pittsburgh. He had been hired as a researcher at the Cancer Institute, and some part of her longed to combine her pharmaceutical experience with the study of organic chemistry.

Her interest is not purely academic. Ultimately, she wants to find better drugs to treat breast cancer. Janjic, who is 30 years old, believes registering at Pitt was part destiny, part decision. In the end, she says she’s pleased with her destiny-decision.

So is Pitt. Janjic’s background in pharmacology and her understanding of chemistry bridges disciplines that collaborate far too infrequently, says Billy W. Day, who is Janjic’s faculty advisor, and an associate professor in the departments of pharmaceutical sciences and chemistry. “I think it’s a big deal that she’s able to understand and perform both chemistry and biology,” adds Day, who is also director of Proteomics Core in the Schools of the Health Sciences. “Those who understand both sides are rare.”

Janjic embodies an emerging kind of scientist, a cross-trained researcher who grasps both the chemistry needed to develop new drugs and the biological know-how to understand what it takes to make an effective drug. “We can make really, really interesting things in the lab that may not work well in the body,” she says. For example, compounds that have therapeutic uses must be easily absorbed by the body and not destroyed by stomach acid.

“We need more students like her,” says Peter Wipf, professor of chemistry. Janjic also bridges Pitt’s upper and lower campuses, Day says, bringing together the Faculty of Arts and Sciences, and Schools of the Health Sciences. It’s the kind of cooperation that has been Day’s dream for many years, he says.

Once upon a time, making new drugs was like playing the lottery. As recently as the early 1990s, a drug company chemist was expected to produce one or two new compounds per week. Only one in thousands would wind up with any real value, says Kay Brummond, an associate professor in the chemistry department. By comparison, winning the Pennsylvania Lottery Daily Number with odds of 500-to-1 was a much safer bet.

All this began to slowly change with breakthroughs by Hungarian researcher Arpad Furka at Eotvos University and H. Mario Geysen, an Australian scientist at drug-maker Glaxo Wellcome (today called GlaxoSmithKline). In the mid-1980s, both men came up with ways to create several compounds at the same time. To use the lottery analogy, instead of a researcher buying one ticket with one set of numbers, imagine that researcher getting hundreds of number combinations for the price of one. Odds of winning the “lottery” in developing an effective drug suddenly improved dramatically because many potential drugs could be made quickly instead of one at a time.

Soon, automated production methods began to be called combinatorial chemistry. The term refers to a variety of techniques, but speed and automation in creating compounds is the result. Instead of a hundred or so new compounds in a year, a chemist using combinatorial chemistry can synthesize hundreds, even thousands of new molecules in the same period of time. “It’s not so much of a lottery anymore,” says Wipf, who is the director of Pitt’s Combinatorial Chemistry Center. “It’s less of a guessing game and more of a game of chess—like playing chess with nature on thousands of boards, simultaneously.”

The center was formed in 1998 with the idea of giving students experience with the latest technology, says Wipf. The center, which is within (yet separate from) the chemistry department, takes up roughly half of the Chevron Science Building’s ninth floor. The center has space for six associates who come from department research groups or outside laboratories. Pitt’s center was born as a collaborative project. This is its defining feature.

When the center was created, Pitt’s Faculty and College of Arts and Sciences; faculty in the Department of Chemistry, School of Medicine, and Cancer Institute; and the Office of the Provost created a template for future collaboration within the University. “It’s a good example of what we do well here at Pitt,” says Provost James V. Maher, pointing out that the collaboration is unique. Agreeing with Maher is Dennis P. Curran, distinguished service professor of chemistry and Bayer professor: “People from the different disciplines have almost operated in a vacuum. That vacuum is collapsing. We’re really in the forefront.”

Partnerships with the departments of pharmacology, biology, and pharmacy have formed, and the center’s collaboration on campus puts Pitt in a class with only a handful of other combinatorial chemistry centers in the country, according to Wipf and Curran. They note that other institutions in this elite group include Harvard University and the Scripps Research Institute. Students like Janjic are quick to notice the cooperative spirit. “This is amazing,” Janjic says.

Last year, Pitt received a $9.6 million grant from the National Institute of General Medical Sciences, which is part of the National Institutes of Health, to develop new chemical methodologies and create “libraries” of more than 50,000 compounds during the next five years. The center grant is one of only two in the nation funded by the institute. (Boston University houses the other center.)

Most exciting, Pitt’s chemical library will contain compounds that are very different from those currently available. Brummond, who is vice director of Pitt’s Center of Excellence in Chemical Methodologies and Library Development, will help devise new ways to make novel compounds quickly. In essence, the center will be inventing manufacturing technology and unique compounds at the same time. That’s quite a feat.

Creating compounds that are entirely different from each other will be a big advance in conventional combinatorial chemistry, which often produces thousands of compounds that are only slightly different from each other. “Many are too similar to be of any value,” says Brummond, winner of the 2003 Chancellor’s Distinguished Research Award. Curran describes the goal of the library project as making “novel compounds from novel chemistry.”

Soon, researchers worldwide will be able to enjoy Pitt’s innovation. Pitt’s Center of Excellence in Chemical Methodologies and Library Development, which is also housed on Chevron’s ninth floor, will make these new compounds available to scientists, Wipf says. As a pioneer in new chemical manufacturing techniques, Pitt will attract still more talented students and skilled researchers, while the compounds will help researchers everywhere with such breakthroughs as creating better drugs to fight diseases or developing more effective agricultural chemicals.

Curran—who received the American Chemical Society Award for Creative Work in Synthetic Organic Chemistry in 2000 and the Chancellor’s Distinguished Research Award in 1999—developed an effective way to identify compounds in mixtures by using fluorous as a separating agent. Fluorous, which comes from the element fluorine, can be solid or liquid. Fluorine is an important ingredient in making a host of things, from rocket fuel to toothpaste, and fluorous molecules are used to “tag” or mark compounds for easy identification within mixtures. Although fluorine was discovered in 1886, Curran was the first person to use it as a tool in chemical separation.

Three years ago, Curran formed Fluorous Technologies Inc., a private company that capitalizes on the chemical separation technique. The company is targeting the $40 billion research and development market for prescription drugs. The list of Fluorous Technologies’ customers reads like a Who’s Who of industry giants, including Merck, Pfizer, Eli Lilly, and Genentech. Small wonder: It costs an estimated $802 million to create a drug and get it through regulatory review, according to the Tufts Center for the Study of Drug Development. Fluorous tagging saves drug manufacturers time and money, which is expected to boost Fluorous Technologies’ sales 10-fold this year to $2.5 million, according to company estimates and TechyVent Pittsburgh, a newsletter produced in cooperation with the Pittsburgh Technology Council.

In addition to Day, Wipf, Brummond, and Curran, those involved in the chemical library project at Pitt are Stephen Weber, professor, bioanalytical chemistry, and director of graduate studies; Scott Nelson, associate professor of chemistry; and John Lazo, Allegheny Foundation Professor and Chair of Pharmacology in the School of Medicine.

Here’s how the research will be done. First, Pitt’s Center of Excellence in Chemical Methodologies and Library Development will create unique compounds that could have any number of commercial or therapeutic uses. A research chemist may one day contact the center about a compound that shuts down a particular protein, which might be critical to the spread of AIDS within the body. Pitt will provide a collection of compounds to the scientist as a starting point for further testing. Another researcher may also ask for the same or a different collection of compounds to learn more about the role of the protein in the spread of the disease. “We would like to make our libraries generally available,” Curran says.

Ordinarily, drugs work by binding to tiny cell receptors, which are inside body cells. Think of receptors as Sears Craftsman open-end wrenches, only much smaller. On a molecular level, drugs work by filling or blocking the tiny openings in these “wrenches.” These tiny drug molecules either activate or keep something from happening inside a cell, much like a key turning a tumbler in a lock.

Hormones, for example, which bind to specific receptor sites in the body, are signaling molecules. As a rule, the tighter the fit, the stronger the bond, the more potent the drug and the less that is needed to create a reaction. That’s why reconfiguring molecular shape is key to new drug discovery. Computer modeling is among the tools being used at Pitt to create the best fit possible for these small molecules.

Take the drug tamoxifen. It has been used for more than 20 years to treat women who have been diagnosed with breast cancer. In 1998, the FDA approved the use of tamoxifen as part of a prevention plan for women with a higher risk of breast cancer. And it works pretty well. A recent study in the medical journal The Lancet found that tamoxifen reduced the incidence of breast cancer by 38 percent in women in this group. Estrogen is believed to spur the growth of breast cancer in some 80 percent of cases. Tamoxifen works by binding at estrogen-receptor sites in breast tissue, essentially starving the tissue of the hormone.

But in a sense, tamoxifen is blind. For instance, the drug also blocks estrogen-receptor sites in the liver, where estrogen normally reduces the production of harmful cholesterol. What’s more, the study in The Lancet found that women taking tamoxifen had a two-fold increased risk of developing uterine cancer, which is much less common than breast cancer. Tamoxifen also has the more common side effects of nausea, vomiting, and hot flashes. For these reasons, women are sometimes reluctant to take tamoxifen. An improved form of the drug would block estrogen receptor sites in, say, breast tissue, but not other tissue, such as bone or liver. Wipf calls the process “making a smarter missile.”

When it happened, Janjic was working alone in her lab with her syringes, notebooks, and glass containers. There was no one to tell. No champagne, no high-fives. Everyone had gone home for Christmas.

She has a key to the lab. And unless she’s in the lab, she says she feels worthless. A “total lab geek,” she says with a laugh. A group of students in the Wipf lab—she was not among them, she quickly notes—had previously prepared 80 compounds. These compounds piqued her interest because they may have estrogen-blocking properties. With that quality comes the tantalizing prospect of a more effective brand of tamoxifen, perhaps leading to a “smarter missile.”

Janjic’s experiment stretched over four days. She wore the lab coat with her name handwritten in ink near the lapel. She worked alone. She used the same care, the same determination, and was moved along by the obsession that guides most of her days in the lab. Then, it happened. In a test using living cells, she found a compound that blocks estrogen. “I was just jumping around, totally nuts,” she says.

The results are “very encouraging, indeed,” Wipf says.

Janjic is buoyed by the possibility that a more effective treatment for cancer may evolve from CK1-183, the name given to the compound. Researchers call CK1-183 a “lead,” a substance that will undergo refined testing and chemical manipulation in order to improve its effectiveness. Animal testing will follow, and, ultimately, it may be tested in people. Even then, it may be years before it’s carried by your local pharmacy. Still, Janjic says the discovery was “like hitting the lottery”—a lottery with the odds in her favor.

Kris B. Mamula is a senior editor of this magazine.

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