Development of drug innovations to treat cancer, leukemia, and malaria

Dr. Vern L. Schramm, Chair and Professor in the Department of Biochemistry at the Albert Einstein College of Medicine of Yeshiva University in New York City, spends his days capturing moments that last only a fraction of a trillionth of a second yet may be critical in designing innovative drugs for diseases like cancer, leukemia, gout, and malaria. Those critical moments are the points where enzyme reactions transition from one chemical state to another. Why are these transitions important?

Biological life depends on chemical transformations that result from the catalytic work of enzymes. By determining enzyme transition states, which are reached when the probability of the reaction moving forward to form products, or return to reactants, is equal, Schramm and his research team can make stable chemical analogues, or mimics, of this moment in the reaction. Using this knowledge, Schramm and his chemistry collaborators in New Zealand develop novel enzyme inhibitors to treat human diseases.

The National Institutes of Health (NIH) has funded Schramm’s analysis of transition states for over 30 years. First, Schramm and his team developed a fundamental understanding of the chemical nature of enzyme transition states. With that knowledge, the research team was ultimately able to manipulate enzyme reactions and develop pharmaceutical drugs.

Working with Yeshiva’s Office of Biotechnology, Schramm and his chemical team at Industrial Research Limited, New Zealand has partnered with BioCryst Pharmaceuticals to generate agents for leukemia. World-wide clinical trials are now being conducted by Mundiphara International to commercialize his products. Additionally, BioCryst Pharmaceuticals has one of Schramm’s compounds in Phase II drug trials for gout. Yet another inhibitor is now in the primate animal stage of testing for malaria.

Schramm’s expertise in transition state analysis has also led to a potential innovative treatment for cancer. He began his investigations for the U.S. Army Medical Research Institute for Infectious Diseases, and currently Schramm is developing an inhibitor for ricin, a highly toxic protein found in the castor oil plant. The army saw Schramm’s research as a means of fighting bioterrorism; Schramm always knew that linking ricin to antibodies could combat cancer. Most toxin-based cancer therapies generally cause severe side effects, prohibiting their widespread acceptance. But Schramm’s research on inhibitors reduces the side effects and increases the efficiency of toxin-based cancer therapy.

By 2015, Schramm anticipates having one or two compounds successfully complete U.S. FDA drug trials and receive approval. He hopes these approvals will demonstrate the success of transition state analogues in drug analysis to the pharmaceutical industry. Additionally, Schramm sees the continued development of strong assays, similar to the innovative test for ricin detection, as an avenue to strengthening future drug developments.

Based on personal experience, Schramm strongly believes that support of basic scientific research often leads to important, unanticipated benefits. Once he achieved an understanding of enzymatic transition states, he could see applications to develop drugs for unmet medical needs. Schramm’s innovative approach to drug design is directly tied to the fundamental chemistry research supported by NIH.