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When Stephen Frye completed his Ph.D. in chemistry at Carolina in 1987, he set out to make a difference.

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Stephen Frye, PhD

As a chemist concerned with hard-to-cure diseases, he spent 20 years at GlaxoSmithKline (GSK), eventually working his way up to Worldwide Vice President of Discovery Medicinal Chemistry.

“When I finished up at Carolina, I felt that instead of going into academics, I’d go into the pharmaceutical industry because it’s always been important to me that I can see the impact of what I’m doing, that the things I do interface with the world,” said Frye.

Times changed, and so did the industry. Frye wondered if the future of drug discovery wasn’t in his chosen path in industry, but in the academic one he left behind. With collaborative basic science coming from every corner of campus, he felt that Carolina could be in the perfect position to make a big impact with translational medicine.

Carolina, it turns out, was interested in the same thing.

In 2007, the Eshelman School of Pharmacy and the UNC Lineberger Comprehensive Cancer Center brought Frye back to Carolina to create the Center for Integrative Chemical Biology and Drug Discovery.

The center was established to take the basic biological discoveries made by scientists who research different diseases and translate those findings into the small-molecule drugs that interact with cellular targets and improve outcomes for people.

At GSK, Frye avidly read basic science papers from academics and even worked with them from time to time. At Carolina, he works side-by-side with them.

This past spring, the center moved its operations into the brand-new Marsico Hall, a state-of-the-art research facility meant to make this kind of collaboration even easier.

“The main thing that I can do here at UNC that I could not do at GSK is to work on a day-to-day basis with physician scientists who see patients, who have an idea that they want to test for a way to treat that patient’s disease,” he said.

Locks and keys

Carolina’s biologists come to Frye with a lock – a biological state that, if it could be changed, would have a beneficial outcome for the patient.

The chemists – Frye and his researchers – look for the key: the small-molecule drug with the right properties to get into a cell and alter its function in a therapeutically beneficial way.

“At the center, the biologist presents a problem and the chemist is the one who has to solve it,” Frye explained. “Can you get a small molecule that’s safe and effective, that can be used in humans, that will modulate the target’s activity, to open the lock?”

Six years ago, shortly after the center opened, Shelley Earp came to Frye with his lock. The professor of medicine was, at the time, head of UNC Lineberger.

“We’d seen something in our biological research that, if we could inhibit it, might be able to treat different kinds of cancers,” Earp said.

Frye’s lab got to work on the keys. The two scientists’ groups met once a month for years, sharing what they’d seen in their own research to get closer and closer to the chemical interaction that would inhibit the target in cells.

The chemists on the project designed and synthesized more than 1,000 different small molecules that were tested at the center, in the Earp lab and in the lab of Doug Graham, a former Earp student and a collaborator at the University of Colorado, Denver.

They found what they needed: potent, metabolically stable and cell permeable inhibitors of Mer tyrosine kinase, which plays a specific role in certain kinds of cancer cells, increasing a tumor’s ability to survive and avoid clearance by the immune system.

One of those cancers is acute lymphoblastic leukemia, a common cancer in children. About 85 percent of children are cured with chemotherapy, said Frye, but they inevitably have lifelong neurological and cardiovascular damage from the chemotherapy.

“One of our beliefs is that we will significantly lower the dose of chemotherapy and still maintain cures for children, and they will have a normal lifespan and health status,” said Frye. “That’s the hope.”

From lab to clinic

Bringing about a desired response is easier in a test tube than in a living thing, said Earp.

“We needed to inhibit the protein inside a cell first and then see if we could do that in an animal, like a mouse,” he explained.

To explore the activity of a novel small molecule in humans requires regulatory oversight by the Food and Drug Administration, the development of a “candidate” (a robust and reproducible synthesis of the potential drug), extensive toxicology studies and the filing of an Investigational New Drug (IND) application.

All that takes money, the type of funding that doesn’t come with traditional grants, said Earp.

“We could license the idea and the candidate to a drug company for development, or we could form a startup here at UNC,” he said. “The latter would allow us to be more involved with the process, so that’s what we did with the help of Don Rose and Carolina Kickstart.”

In 2013, Frye, Earp and Graham founded Meryx Inc. to develop the Mer tyrosine kinase inhibitor they discovered in the lab into a therapeutic drug used to help treat critically ill patients. So far, the results are good in mice, rats and dogs, said Frye.

“We’ve got the compounds, and we’re at the point where we need to raise additional money to get the compound into clinical trials,” he said. “If things go well, we’ll have an IND next May or June and a clinical trial here at UNC in adults and children with leukemia.”

To find the right key for a lock, you need to commit long-term, said Frye, which is something that can go by the wayside in the pharmaceutical industry.

“If you’re focused on next quarter’s sales figures, research becomes an expense center. What I do this quarter will not affect the sales this quarter, it will affect the sales 15 years down the road,” said Frye.

“The culture of the pharmaceutical industry has changed so that it’s hard to maintain the focus for the time it takes to be successful. The only way you’re going to be successful is to have a long-term view and create an environment in which people can do outstanding collaborative science.”

Finding the right mix

Frye is eager to see Earp’s many decades of research translated into the clinic. He’s cautiously optimistic, but he doesn’t want to count chickens before they hatch.

“I’m certainly proud of the people I work with and what we’ve been able to accomplish, but right now, I’m hopeful,” said Frye. “When I see the results of the clinical trial, I’ll be proud.”

Drug discovery can take 10 to 15 years. Often, what keeps that momentum going, Frye said, is a successful relationship. With the juxtaposition of biology and chemistry so essential to drug discovery, it helps if the biologist and chemist get along.

“I’ve been lucky enough to have been involved in a number of projects that have resulted in FDA-approved medicines, and in every example there were key chemists and biologists who were champions for the target and drove the concept forward,” he said. “Shelley, Doug and I have built that type of partnership.”

Earp said that, by nature, biologists are explorers, often spending whatever time is necessary to follow a path to its conclusion. When Frye came back to Carolina, he brought not only his vision, but also a devotion to project deliverables.

“If you’re going to work with someone for years on such a long collaboration, it helps to have the same values, the same excitement and willingness,” said Earp. “The great thing about Stephen is that he also has tremendous organization skills that keep us on task.”

Twenty years in the pharmaceutical industry have shown Frye what works best. When the scientific and personal relationships click, a long-term research effort can thrive.

“One of the really important things is that you like and enjoy the people you work with, just like every other endeavor,” he said. “Shelley and I have built a strong relationship. He’s a great scientist and we’re going to make this work partly because of that relationship.”