Ferguson Group

Research

I enjoy applying chemistry to solve problems in biology, especially those related to drug design and discovery. Being a chemist by training, my research is necessarily collaborative, involving labs from biology, pharmacology, and the clinical sciences. Although our projects may focus on different biological targets, our role is consistent. We study relationships between molecular structure and biological function (typically small molecule – large molecular interactions) to rationalize the design of improved therapeutics using SAR studies, biochemical assays, and structural analyses (including X-ray crystallography, molecular modeling, and spectroscopy).

When I arrived at Minnesota in the early 90’s, the initial focus of my lab was on opioids and G protein-coupled receptor function. Over the years, we made substantial contributions to this field and were one of the first groups to apply structure-based models to the design of selective opioid agonists and antagonists. We also performed seminal work on salvinorin, a potent kappa opioid agonist that gained popularity in the street drug culture for its hallucinogenic properties. Using a combination of site directed mutagenesis studies and computer modeling, we described a unique binding site model that placed salvinorin A in a pocket that shares limited overlap with traditional kappa selective opiates. This orientation is shown in Figure 1 and was published in the Journal of Medicinal Chemistry.

Although I continue to work on projects involving opioids and other drugs of abuse, my lab has become more involved in cancer research. Our transition into the design of anticancer agents happened somewhat by chance. We had synthesized a series of constrained analogs of a highly potent delta opioid antagonist with a diaryl amino core structure. Interestingly, the heterocycles we developed never showed the desired potency as analgesics, but did show good activity when cross screened for antiviral and anticancer activity. While it took several years to complete, we have successfully described a small, diverse chemical library with promising activity against a variety of targets. The screening of this library led to the discovery of the first small molecule lead compounds with promising activity against the West Nile Virus as well as a new set of topoisomerase inhibitors with a anti-Herpes activity. My lab has further shown the latter function as catalytic inhibitors of topo activity (not poisons) and block topo association with DNA by intercalation. The compounds have been found to be active in both in vitro and in vivo anticancer assays and showed excellent efficacy in an mouse glioblastoma model following oral administration. This project is particularly interesting to us since we have a long standing history in the simulation and analyses of the structural properties of DNA complexes. In fact, we applied this expertise in concert with DNA binding studies and high field NMR work to build a structural model that explains the molecular basis to catalytic inhibition of topo II.

Our most recent work is perhaps the most exciting. As part of our pre-clinical work on treating gliobastoma with topoisomerase inhibitors, we were asked if it would be possible to synthesize a number of Toll-like receptor (TLR) agonists for the development of a cancer vaccine. Clinical trials have shown that patients receiving combination therapies including vaccines based on tumor cells or lysates showed better outcomes than those receiving chemotherapy alone. The University of Minnesota is a leader in the field of autologous cancer cell-based immunotherapy and has completed clinical trials for treating glioblastoma in humans and several canine meningioma trials. Autologous cancer cell vaccines use the patient’s own tumor cells as the antigen which is formulated as a cell lysate or apoptotic bodies as an injectable. One of the primary challenges to cancer vaccination is the rapid development of tolerance and suppression of tumor specific cytotoxic T cell function. The key to defeating tolerance are the Toll-like receptors. TLR ligands, such as the TLR-7 agonist imiquimod, stimulate the immune response and are capable of increasing the immunogenicity of antigen presenting cells (APCs) by several orders of magnitude. TLR activation triggers the NF-kappaB mediated transcription of cytokines and chemokines, leading to a robust response in the generation of antigen specific T cells (both CD8+ and CD4+ cells). Our lab has shown that more potent TLR adjuvants can be created by co-stimulation of TLR-7 and -8. This is not surprising since the “natural” ligand for both these subtypes is RNA (derived from viral pathogens). Based on the imidazoquinoline scaffold of imiquimod, our lab developed a series of highly substituted analogs that show a clear SAR in producing cytokines and triggering TLR-7 and -8. We have also begun to establish rules for selectivity of these ligands for TLR-7 and -8 and published seminal work relating structure to function in generating cytokines that are critical to an antigen specific immune response.

Our lead compound 528 has entered into canine clinical trials for treating meningioma. This project is a partnership between my lab, Liz Pluhar’s group in the veterinary school, and Mike Olin’s lab in Pediatrics. The first dog treated was batman and he remained tumor free until he died of natural causes (See a video of Batman below.)