Note: this article first appeared in the Spring 2014 issue of PittPharmacy.
Imagine a world in which science could customize medications to interact with a person’s unique enzymes, metabolism, and other biomechanics to zero in on a disease with minimal side effects — a drug specifically tailored to that patient, instead of an off-the-rack, one-size-fits-all approach.
That is the space in which Xiang-Qun (Sean) Xie works, the scientific horizon he is cresting. Using a formidable background combining structural biology, computational chemistry, and medicinal chemistry, the Shanghai-trained Xie functions as the de facto chief executive officer of a School of Pharmacy group that is rapidly pursuing drug development at its most sophisticated level to date.
Since 2006, when he was recruited to Pitt from the University of Houston, Xie has built his lab around three distinct, yet interdependent, groups: one specializing in biology, one in chemistry and one in computation, which integrates the other two. The computation group identifies potential compounds for development, which are then validated by the biology group and processed by chemistry to raise potency and lower toxicity.
It’s a powerful combination, one that has already won approval for five patents.
“I try to operate my group in a productive way, because we have about 12 people,” says Xie, “I run my group like a small biotech company … I want to reach out to companies, even investors, to see whether we can license our patents.”
In pursuit of the new
At stake is the potential to more deftly and efficiently create new drugs, and also to repurpose existing compounds to treat diseases other than those for which they originally were developed. To do that, Xie creates cloud computing models and a sourcing chemogenomics knowledge base that perform a variety of functions. For example, they can screen libraries containing hundreds of thousands of compounds, whittling them down to a handful with characteristics worth investigating further for a particular use. Xie’s approach lops significant time and expense from traditional screening methods, while increasing success rates by more accurately predicting how a substance might respond under various conditions.
In addition to his status as a professor of pharmaceutical sciences and a faculty member with the Drug Discovery Institute, Xie also directs the Computational Chemical Genomics Screening (CCGS) Center and is a prolific collaborator with scientists both at Pitt and elsewhere.
In fact, it was the University’s collaborative atmosphere that convinced Xie to move to the School of Pharmacy.
“At that time, Pitt was forming the Drug Discovery Institute,” he recalls. “The environment was very appealing to me because I could use my expertise and integrate it well.”
One tool Xie’s lab has built to encourage collaboration is a database of all disease-specific chemical genomics, from proteins and genes to drug molecular levels. Researchers worldwide can access the information as they develop treatments: What the molecule interacts with, what metabolic enzyme is used, potential side effects, and potential new uses.
Widening the impact
Xie’s group is working to identify and develop molecules for a variety of diseases, including a project with Children’s Hospital of Pittsburgh to target diabetes and another with the U.S. Food and Drug Administration to use technology for allergy prediction modeling. An initiative tied to Alzheimer’s disease, which involves multiple targets due to the complexity of the condition, seeks to integrate all marketed drugs, compounds, and reported molecules in clinical trials.
One disease Xie’s group is studying is multiple myeloma, which is a cancer of the plasma cells in bone marrow. The group has discovered novel chemical agents in collaboration with former Pitt clinician David Roodman.
Working with Barry Gold, who chairs the Department of Pharmaceutical Sciences and is co-director of the Drug Discovery Institute, Xie’s lab developed a lead compound to treat the disease through its discovery of a small molecule.
“His role is vital,” Gold says of Xie, whom he helped to recruit to the University. “He has his own areas of research, but he has a big impact on lots of people around campus. The bottom line is: If you want to treat human disease, you have to come up with a drug. People take medicine to treat disease. That means you have to have people like Sean and chemists to synthesize molecules that can be evaluated and, hopefully, eventually get into the clinic.”
Ever curious, Xie and his team are often experimenting, refining, finding new uses for their skill sets: predicting how well a compound can cross the blood-brain barrier. Developing a graphics processing unit-accelerated computing chemical library. Studying natural products to identify their potential targets in complex disease states. Customizing compounds is another passion of Xie’s. When a single drug hits multiple targets within the body, the unintended targets can result in side effects. Different programs can help predict these side effects even as the group works to narrow its target.
Xie also uses his software, TargetHunter, to repurpose old drugs for new applications. For example, he cites sildenafil™ citrate, which is sold most famously as Viagra but also treats pulmonary arterial hypertension and has shown promise in treating altitude sickness.
A science matchmaker
A secondary feature of TargetHunter recently introduced by Xie’s lab is an embedded geography tool, BioassayGeoMap, which is meant to help facilitate collaboration. When a user clicks on the predicted target, the program creates another window mapping other scientists who have published papers studying a similar problem and may help to validate the target experimentally, along with email information lined to the National Institute of Health’s PubMed program. These links encourage authors to work together, accelerating research production.
“Right now, we made it open access to encourage people to come back with feedback,” Xie says.
Such projects reflect a hallmark of Xie’s research, says Gold:” He loves to work with other scientists, which is fortunate, since his expertise is in such high demand. His dynamic, energetic style excites colleagues, which is often a key ingredient in groundbreaking research.
“In collaborative research, a lot of it has to do with personalities,” explains Gold. “You can be an absolute genius, but sometimes very difficult to work with. Sean is pretty easy, very cooperative. And that makes a difference in successful collaboration.”
What lies ahead
In addition to his research, Xie teaches in three courses, mentors six graduate students, and serves as the associate editor of two journals as well as the guest editor for the American Association of Pharmaceutical Sciences.
“I like to give lectures, because I find it’s more interesting to interact with students,” he says. “To do research is one thing, but if you want to pass your knowledge to new people, it’s more stimulating to teach”, he adds.
Future pursuits may include the development of an exchange program between the School of Pharmacy and universities in China. Xie is also the principal investigator for a proposal submitted to the NIH in September for a new center that would develop technology to integrate government research into drug abuse, in hopes of finding a compound that would address the problem. The team includes Lirong Wang, assistant research professor/scientific administrator of the CCGS center; Ivet Bahar, John K. Vries Chair in Computational & Systems Biology at the School of Medicine; and Eric Xing and Wei Wu from Carnegie Mellon University.
Despite widely publicized congressional cutbacks to the NIH, Xie is optimistic that his research will continue to flourish, possibly with the help of the pharmaceutical industry and private investment.
“We try to diversify,” he says.
Attracting new talent
That atmosphere, and the opportunity to work with a scientist of Xie’s caliber, was one strong draw for Hyun Jin Kim, assistant professor of pharmacy and therapeutics, who came to the School of Pharmacy in January 2013.
Kim earned his Ph.D. in bioengineering with an emphasis on computational biology. Since his arrival at Pitt, he has placed more emphasis on computational clinical pharmacology, and he considers Xie a mentor.
“It’s an emerging field, and there are a lot of exciting opportunities waiting to be explored,” says Kim, whose research interests include developing computational methods that work in conjunction with “wet lab” research (where scientists conduct physical experiments), to reduce or prevent risks from drugs before they go to market.
Kim describes his research as more systems-oriented, but his hope is to integrate his work with smaller-scale biological and chemical research to create a more holistic approach toward drug development. The idea is to better understand the interaction between individual patients and pharmacological interventions.
