Krzysztof W. Pankiewicz, Ph.D.

Professor, Center for Drug Design
Senior Associate Director, Center for Drug Design
Center for Drug Design Advisory Commitee
Professor, Department of Medicinal Chemistry

Contact information
 
Office: 7-215 Phillips Wangensteen Building
Phone: 612-625-7968
Fax: 612-625-8252 E-mail: panki001@umn.edu

Education
 
M.Sc., Warsaw Polytechnic, Warsaw, Poland, 1966
Ph.D., Polish Academy of Sciences, Lodz, Poland, 1979

Chronic myelogenous leukemia (CML) is a cancer which can be difficult to treat. The cancer cells require a protein called IMP-dehydrogenase (IMPDH) for their uncontrolled growth, but two slightly different forms of the protein are made by human cells. The Type II form is produced in large amounts by CML cancer cells, while the Type I form, a "housekeeping" protein, is the primary form found in normal cells. Both forms require a general helper molecule called nicotinamide adenine dinucleotide (NAD) to carry out their function, but they have subtle structural differences which should make it possible to specifically target the Type II protein.

Shown on the right is part of the structure of the Type II protein (light blue, gray, and yellow colors). The molecules IMP, RMP, MPA, and MAD are shown at the locations where they interact with the protein. IMP is the molecule which is normally processed in the body. Part of the processing involves removing a hydrogen from IMP, which is why the protein is called IMP dehydrogenase.

The other three molecules in the figure all block the activity of IMPDH. As you can see from the figure, RMP works by filling the space where IMP would normally bind. MAD and MPA fill the space where the helper molecule NAD would normally bind. Unfortunately, these molecules are not specific for Type II IMPDH. Therefore, cancer cells with Type II IMPDH and healthy cells with Type I IMPDH may both be harmed by these molecules.

We focus on designing NAD analogs that take advantage of the structural differences between the two forms. We hope that these compounds bind and fill the NAD binding pocket on the Type II protein but not the Type I protein.

We have two antibiotics projects. The first involves new treatments for tuberculosis, which is estimated to be present (usually in a dormant state) in one third of the global population. Activation of dormant tuberculosis infections can occur in patients with weakened immune systems, as in the case of AIDS.

Isoniazid (INH), an old "first line" treatment for tuberculosis, is a small molecule which reacts inside the bacteria, linking itself to the general helper molecule nicotinamide adenine dinucleotide (NAD). The INH-NAD complex inhibits synthesis of the bacterial cell wall, preventing bacterial growth. Recent studies have shown that drug resistant tuberculosis does not carry out the reaction which links INH to NAD, and therefore cell wall growth is not blocked. We are preparing NAD analogs that mimic the properties of INH-NAD, which would bypass the need for the linking step inside cells. These molecules may be active against drug resistant tuberculosis.

Our second project is similar to the leukemia research described above. Substantial differences exist between the NAD binding site of human IMPDH and IMPDH enzymes from other organisms. We are using these differences to design inhibitors that will block activity of the IMPDH protein in disease-causing organisms without affecting human IMPDH. Target organisms include bacteria, fungi, and protozoa.

We continue our search for drugs, including nucleoside phosphonates, which prevent certain types of viruses from making copies of their genetic material. We are also synthesizing analogs of mycophenolic acid (MPA) as potential anti-viral drugs. MPA is one of the most effective agents against the West Nile virus, but we hope to improve its properties.

A detailed research description and publication list is also available.