NIH Grant Establishes CMLD at KU

With the awarding of a five-year, $9.57 million grant from the National Institutes of Health, the University of Kansas recently became one of only four Combinatorial Methodology and Library Development Centers of Excellence in the United States. The other centers are located at Boston University, the University of Pittsburgh, and Harvard. Fifteen investigators will take part in the research12 at KU, and one each at the University of Missouri at Kansas City, Iowa State University at Ames, and Deciphera, Inc., a Lawrence-based company. Each center will develop large repositories or libraries of molecules, using tools developed in the burgeoning science o1 combinatorial chemistry.

In the not too distant past, a chemist could make molecules only one at a time. If one molecule didn't accomplish the desired function, then the chemist would systematically make slight variations of that molecule in the hopes of striking closer to the mark. Called analoging, this laborious process was woefully inadequate when applied to drug development. Jeff Aube, KU professor of medicinal chemistry and the Principal Investigator for KU's Combinatorial Methodology and Library Development Center (KU-CMLD), said: "Identifying a molecule with drug potential in this traditional way amid all the candidates was like finding a needle in a haystack. It's common for a medicinal chemist to synthesize about 10,000 different molecules before a single drug reaches the bedside."

Combinatorial chemistry has shaved countless frustrating hours from the molecular development process. Not only can chemists create thousands, even millions of molecules at a time, they can also identify each and investigate its biological activity.

NIH has designated chemical library synthesis as one of the key technology areas on its Roadmap for Medical Research initiative, putting KU at the center of the organization's efforts to take drug development to a new plateau. Because it is a highly technological rather than conceptual science, combinatorial chemists in academia have had difficulty funding their work by traditional methods. Consequently, most of the growth in the field until recently had occurred in the industrial sector. The NIH realized that technology had been slipping through the cracks, and they committed to funding the increasingly important work of compiling molecular libraries in the academic environment.

Several key factors moved KU to the top of the NIH's list of center grant applicants. Many individuals listed on the grant application had distinguished themselves in the area of combinatorial chemistry. "Another factor that allowed us to compete successfully with a lot of outstanding departments and universities was KU's substantial history in drug discovery and development," Aube said. This background puts KU-CMLD researchers in a position to cull from the enormous number of possible molecules, those with physical properties that make them likely to result in useful pharmaceutical compounds. "That's something none of the other centers have. They are all good chemists, brilliant people, but they don't have this particular background. Not only do we know how to make drugs, but we have a good sense of what to make." John Schwab, who directs the CMLD program for the National Institute of General Medical Sciences, one of 20 NIH agencies, also lauded this strength. "KU brings a unique and valuable medicinal chemistry perspective to this program. This will be the only one of our centers with a historical commitment to the development of therapeutically active molecules."

The KU-CMLD is divided into four large areas of research. Keith Buszek of UMKC is an organic chemist who will lead the natural products privileged structures project. Privileged structures are general classes of structures that have been shown to be useful as probes in more than a single drug class. An example would be benzodiazepines, which are useful as anxiolytics (think Valium) or as antipsychotic agents. Buszek has a research specialty in medium rings, which are cyclic organic compounds derived from natural products that have pharmacological potential. This group will use nature as an inspiration for the development of libraries of drug-like molecules.

Another project focuses on organometallic chemistry. Researchers will use modern metal catalysts to promote library synthesis. The third project, called biomimetics, will focus on making libraries of compounds based on molecules naturally found in the body, such as peptides or carbohydrates. The hope is that either one of those two classes of compounds will also be a fruitful area of exploration for deriving drug-like molecules.

More technologically oriented than the others, the fourth project is called phase trafficking. In short, researchers will develop innovative ways of guiding molecules to places where they can accomplish such things as efficiently using and then ridding themselves of reagents and catalysts.

The founding of the KU-CMLD puts its researchers in the unique position of being not only consumers of the technology of combinatorial chemistry but innovators as well. With the enormous number of molecules to be contained in its libraries, the KU-CMLD has already inspired hopes of interdisciplinary collaboration between researchers and institutions. For example, at KU's Center for Cancer Experimental Therapeutics, led by KU-CMLD grant applicant Gunda Georg, researchers will use the molecules developed by the CMLD to find new drugs to fight cancer. "All the compounds the Center finds will come to us," said Georg. "This effort will allow us to find new pharmacological tools and potentially new drugs." William B. Neaves, president and CEO of the Stowers Institute for Medical Research in Kansas City, Missouri, is also excited by the potential of this new collaboration. Neaves said, "Aube and his colleagues in the center will greatly expand the inventory of small molecules with the potential to influence these targets therapeutically."

Aube sees a long and fruitful future for the KU-CMLD. "Our hope is that after the initial five-year grant, we'll be funded for an additional five years. After a decade of operation, we'll ideally be self-supporting. My greatest hope is that this facility will become part of the scientific landscape-that many people will use it on a regular basis and not think twice about its existence. That's what any good new technology should do, just become a part of the overall landscape." •