The Path to a New Drug

Center helps researchers take the first steps on the long road from discovery to treatment 

Say you are a researcher who has spent years studying a disease. You have finally identified the protein that might be causing things to go awry in the cells. Good. And you are pretty sure that if you could manipulate that protein’s activity with a specific drug compound, it might change the course of the disease. Even better. Now what?

For a growing number of researchers at Cincinnati Children’s and the University of Cincinnati (UC), that question is answered with a call to the Drug Discovery Center (DDC). The center is a scientist’s dream library of drug-like compounds, located just miles from the medical center.

Its director, Ruben Papoian, PhD, is one of several DDC scientists who earned his stripes in the pharmaceutical industry. He combined that industry experience with a love of academic pursuit to help researchers bring about new drug discoveries.

Papoian watches over the holdings – some 340,000 drug-like compounds that occupy nearly 3,000 square feet of space. The compounds were donated to Cincinnati Children’s and UC by Procter and Gamble Pharmaceuticals when the company dissolved its pharmaceutical division a few years ago. They negotiated an agreement to transfer the assets and launched the Drug Discovery Center in 2007.

“We’re one of the few academic centers with a pharmaceutical-quality compound library, developed and designed by a pharmaceutical company to get drugs on the market,” Papoian says.

The center works with academic and industry scientists in this country and in Europe to begin the process of translating research findings into marketable treatments. While Papoian is justifiably proud of the help the DDC provides to researchers, he is keenly aware of the fact that it is only the start of a long and costly journey.

How it works

Researchers from a variety of disciplines at Cincinnati Children’s use the center. They come seeking compounds that will act on “drug targets” – cellular or molecular structures they have identified as potential culprits in the disease being studied.

“The researcher comes to us and says, ‘I’ve identified this protein and if there’s some way we can modulate its activity, I think it will have the potential for a therapeutic effect on the disease process,’” Papoian says.

The DDC team then screens the library against the identified target to predict which compounds might work most effectively.

“A researcher might want to test anywhere from 5,000 to 50,000 compounds. Some companies will screen against the entire library. You can’t do that manually,” Papoian explains. “The compounds are spread out among 900,000 vials.”

Searching the stacks

The search for the right active compounds is made easier by a $2.8 million high-throughput screening system (HTS), purchased for the center by Cincinnati Children’s with Ohio Third Frontier grant funds. It allows rapid sorting from among the library’s vast holdings, each bar coded for accurate retrieval and identification. The HTS system looks for compounds best able to affect the target, based on assays the researchers provide.

Just the start

against an identified biologic target is promising, but only the first step, Papoian explains. There are many other factors and steps to be considered – and years of additional studies – before a drug can even come close to consideration for human use.

“In academic research, it’s called ‘the valley of death,’” Papoian says. Traversing the valley can take four to eight years at a minimum to screen compounds and arrive at a drug that’s a candidate for clinical development.

“So what needs to be done next,” he explains, “is that the investigators find a funding mechanism, so they can take these compounds and bring the medicinal chemistry optimization to make them more and more like drugs.”

This part cannot be automated. It requires real, live chemists who tinker with the compound and send it back to the researcher. The researcher then tests it to see if the modifications make the compound better. And back and forth it goes until it is ready for animal testing. Animal testing is where the rubber meets the road, pharmaceutically speaking.

“What you test in vitro has nothing to do with metabolism,” Papoian says. “As soon as you get it into an animal, it might be broken down immediately and just excreted from the body. We don’t know if it’s going to cross the blood-brain barrier. It has to get through your stomach intact and then it’s got to be absorbed by your intestines to get into the circulation and then get into the cells and reach the target. And it can’t make you worse than your disease.”

This stage is crucial to a researcher because if a drug works in an animal model, it is more likely to attract interest – and funding – from pharmaceutical as well as venture capital companies.

Once there is sufficient evidence that the drug works effectively in an animal model, it can be considered for pre-clinical development, another expensive and somewhat lengthy process that, in this country, is strictly controlled by the Food and Drug Administration (FDA). The administration itself attested to the difficulties of getting drugs to market in a 2004 report.

“A new medicinal compound entering Phase 1 testing, often representing the culmination of upwards of a decade of preclinical screening and evaluation, is estimated to have only an 8 percent chance of reaching the market,” the report stated. It went on to say that this rate had not improved since 1985.

Looking to the future

Finding the compounds that will potentially act. But there are some positive signs. Papoian points to the creation earlier this year of the National Center for Advancing Translational Sciences (NCATS) by NIH director Francis Collins. One of the NCATS’ stated goals is to “re-engineer the pipeline for diagnostics and therapeutics discovery and development.” Papoian believes that could mean more funding for researchers whose findings have true therapeutic potential.

Despite the challenges, Papoian says academic medicine will continue its pursuit of breakthrough drugs to treat and cure disease and will continue to define success in that pursuit differently.

“We have more chances for success because researchers can generate some active compounds and use them as molecular probes.