MERIT Award Recipient: Paul A. Wender, Ph.D.
Synthetic Studies Related to Cancer Research/Treatment
Our research program involves studies in chemistry, biology, and medicine. We place special emphasis on both the design of novel therapeutic drug candidates, and the development of new strategies for the efficient synthesis and evaluation of these molecules. The research supported by this grant is focused on molecules that are selected because of their unique biological activities and consequently their potential to lead to new therapeutics for treating cancer and other diseases.
One part of this program is directed at bryostatin, a marine natural product that is now in human clinical trials. Bryostatin has a unique range of activities, including the ability to trigger a programmed cell death pathway called "apoptosis" in cancer cells, providing a means to achieve selective elimination of cancer cells in the presence of normal cells. Bryostatin also reverses a cellular process called "multidrug resistance" that can allow cancer cells to neutralize the effects of entire classes of drugs; reversing multidrug resistance could therefore be used to enhance the efficacy of many anticancer drugs. Bryostatin can also bolster the immune system, which could minimize secondary problems like opportunistic infections that are often encountered by cancer patients as a result of the effects of some cancer chemotherapies on the immune system.
Unfortunately, the supply of bryostatin in nature is limited, and thus far it cannot be supplied through total chemical synthesis. Thus, both clinical studies and research on bryostatin are hampered by the severely limited availability of the agent. We have proposed that the promising activity of bryostatin is actually due to only a subset of its structural features, and we have now produced simplified molecules that we can synthesize in a practical fashion and optimize for clinical performance. Our current test agents work as well as or better than bryostatin in binding, cell assays, and in preliminary animal studies. In this program we intend to advance this approach to the design, synthesis and biological evaluation of bryostatin analogues that would be even more selective than our current candidates in interacting with their cellular targets. Since each of these targets is coupled to major therapeutic challenges (cancer, cardiovascular disease, neurodegenerative disease, etc), the identification of selective agents could produce leads for new therapeutic approaches to these problems.
A second objective of our laboratory program is to identify the basis for the unique biological activity of apoptolidin, which is one of the most selective agents studied in the human cancer cell line screen of the National Cancer Institute. Such selectivity, the ability to eliminate cancer cells while not affecting normal cells, is a key goal of cancer research in the 21st century. We have identified new and more potent analogues of apoptolidin from a fermentation source. We intend to characterize these and other new agents, and to determine the structural basis for their activity as a prelude for advancing these compounds toward clinical trials.
In a third part of our research program, we are using novel chemical reactions to create new molecular entities designed to activate or inhibit a class of cellular enzymes called kinases. Kinases regulate a wide range of normal and abnormal cellular events, many coupled to proliferative diseases like cancer. This program thus delivers new and efficient ways to make novel biologically active molecules designed to regulate key cellular therapeutic targets.
The fourth arm of our research effort is directed at a grand challenge in chemistry, biology, and medicine, namely developing systems that would enable or enhance passage of drugs and probe molecules across biological barriers, thereby making the drugs and probes more effective. This is achieved by attaching the drug or probe to a molecular transporter, a molecule that facilitates passage across a biological barrier (skin, cell membranes, etc). These studies will focus on investigating the mechanism of uptake of transporters through single molecule studies, and on the synthesis and evaluation of new transporters, including their ability to enter cells and tissues and release drugs or probes at therapeutically meaningful levels.