David M. Ferguson, Ph.D.
Professor and Director of Graduate Studies
University of South Florida
Postdoc., University of California, San Francisco
7-125 Weaver Densford Hall, 308 Harvard St. SE
University of Minnesota
College of Pharmacy
Department of Medicinal Chemistry
8-101 Weaver-Densford Hall
308 Harvard St. SE
Minneapolis, MN 55455
Our lab is interested in the design and development of anticancer agents that target topoisomerase (topo) II. Most topo II anticancer drugs are referred to as poisons because they function by trapping the cells DNA in a complex, thereby terminating DNA replication. Well known poisons include doxorubicin, etoposide, mitoxantrone, and amsacrine. While these compounds have proven their utility in the war on cancer, they are highly toxic and mutagenic, greatly limiting their therapeutic outcome. A second class of compounds that inhibit topo II activity are referred to as catalytic inhibitors. This group of compounds functions by disrupting or blocking the enzymes association with DNA or by disrupting processing of the DNA by enzymes involved in the topo-DNA cycle. Unlike poisons which are known for their antitumor activity, catalytic inhibitors are used for a variety of applications (including cardioprotectors and antineoplastic agents) and tend to show a lower toxicity. We have recently discovered a novel series of catalytic inhibitors of topo II that show broad spectrum activity in stopping cancer cell proliferation. The lab is currently applying synthetic medicinal chemistry to explore the structure-based mechanism of DNA binding and topo inhibition as well as the requirements for in vivo activity.
Our lab has a long history of innovation in the field of opioid ligand design and development. We developed and described some of the first ligand-receptor models that explained the structural basis to selectivity of mu, delta, and kappa opioid receptors. These models have been applied over the years for virtual screening, ligand design, and in the development of mechanisms of signal transduction. Our work in modeling selectivity sites within the delta and kappa opioid receptor helped guide the design of the potent kappa antagonist guanidinyl naltrindole (GNTI). This was one of the first opioid ligands to be a priori designed using structure-based arguments derived from receptor models. Our lab is also interested in the natural product salvia divinorum or “Sally D” which contains the psychoactive salvinorin A. Salvinorin is a non-nitrogenous opioid ligand with unique pharmacological properties. Our work combining ligand binding-mutagenesis studies with molecular modeling has led to the development of a novel binding site model that has helped define the structural basis to recognition and selectivity of this natural product.
- structure based drug design
- synthetic organic and medicinal chemistry
- anticancer agents
- computational chemistry
- Pharmacy Teacher of the Year, University of Minnesota 2008/2009/2010
- President's Distinguished Faculty Mentor, University of Minnesota 1999/01
- James A. Shannon Directors Award, National Institutes of Health 1996/97
- Advisor, Merck Research Scholar Program, AACP 1996/97
- Pharmacy Teacher of the Year, University of Minnesota 1996/97
- University Honors Lecturer, CLA, University of Minnesota 1992/1993
- Bush Program in Teaching Excellence, University of Minnesota 1991
- Minnesota Supercomputing Institute, Fellow, University of Minnesota 1991-present
Schiaffo, C. E.; Shi, C.; Xiong, Z.; Olin, M.; Ohlfest, J. R.; Aldrich, C.A.; Ferguson, D. M. Structure–Activity Relationship Analysis of Imidazoquinolines with Toll-like Receptors 7 and 8 Selectivity and Enhanced Cytokine Induction. J. Med. Chem. 57, 339-47, 2014.
Ferreira, R.; Artali, R.; Benoit, A.; Gargallo, R.; Eritja, R.; Ferguson, D. M.: Sham, Y.; Mazzini, S. Structure and Stability of Human Telomeric G-Quadruplex with Preclinical 9-Amino Acridines. PLoS ONE 8 (3): e57701, 2013
Shi, C.; Xiong, Z.; Chittepu, P.; Aldrich, C. C.; Ohlfest, J. R.; Ferguson, D. M. Discovery of imidazoquinolines with Toll-Like Receptor 7/8 independent cytokine induction, Med. Chem. Lett., 3, 501-4, 2012.
Giri, R.; Goodell, J. R.; Xing, C.; Benoit, A.; Kaur, H.; Hiasa, H.; Ferguson, D. M. Synthesis and cancer cell cytotoxicity of substituted xanthenes, Bioorgan. Med. Chem., 18,1456-63, 2010.
Oppegard, L. M.; Ougolkov, A. V.; Luchini, D. N.; Schoon, R. A.; Goodell, J. R.; Kaur, H.; Billadeau, D. D.; Ferguson, D. M.; Hiasa, H. Novel acridine-based compounds that exhibit an anti-pancreatic cancer activity are catalytic inhibitors of human topoisomerase II. Eur J Pharmacol. 602, 223-9, 2009.
Gálvez-Peralta, M.; Hackbarth, J. S.; Flatten, K. S.; Kaufmann, S. H.; Hiasa, H.; Xing, C.; Ferguson, D. M. On the role of topoisomerase I in mediating the cytotoxicity of 9-aminoacridine-based anticancer agents, Bioorgan. Med. Chem. Lett., 9, 4459-62, 2009.
Labello, N. P.; Neres, J. Bennett, E. M.; Ferguson, D. M.; Aldrich, C. C. Quantitative Three-Dimensional Structure Linear Interaction Energy Model of 5’-O-[N-(Salicyl)sulfamoyl]adenosine and the Aryl Acid Adenylating Enzyme MbtA. J. Med. Chem., 51, 7154–7160, 2008.
Goodell, J. R.; Ougolkov, A. V.; Hiasa, H.; Kaur, H.; Remmel, R.; Billadeau, D. D.; Ferguson, D. M. Acridine- Based Agents with Topoisomerase II Activity Inhibit Pancreatic Cancer Cell Proliferation and Induce Apoptosis, J. Med. Chem., 51, 179-82, 2008.
Kane, B. E.; Mc Curdy, C. R.; Ferguson, D. M. Toward a Structure-Based Model of Salvinorin A Recognition of the K-Opioid Receptor, J. Med. Chem., 51. 1824-30, 2008.
Kane, B. E.; Grant, M. K. O.; El-Fakahany, E.; Ferguson, D. M. Synthesis and evaluation of xanomeline analogs—Probing the wash-resistant phenomenon at the M1 muscarinic acetylcholine receptor. Bioorg. Med. Chem., 16, 1376-92, 2008.