Krysztof Pankiewicz

Professor & Senior Associate Director, Center for Drug Design

Professor, Department of Medicinal Chemistry

Email: panki001@umn.edu

Phone:(612) 625-7968

Education

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

Research Interests

Treatment of Chronic Myelogenous Leukemia

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.

Antibiotics

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.

Antiviral agents

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.

Selected Recent Publications

• Bonnac L, Gao GY, Chen L, Felczak K, Bennett EM, Xu H, Kim T, Liu N, Oh H, Tonge PJ, Pankiewicz, KW. 2007. Synthesis of 4-phenoxybenzamide adenine dinucleotide as NAD analogue with inhibitory activity against enoyl-ACP reductase (InhA) of Mycobacterium tuberculosis. Bioorg. Med. CHem. Lett. 17(17): 4588-91.
• Chen L, Gao G, Bonnac L, Wilson DJ, Bennett EM, Jayaram HN, Pankiewicz KW. 2007. Methylenebis(sulfonamide) linked nicotinamide adenine dinucleotide analogue as an inosine monophosphate dehydrogenase inhibitor. Bioorg. Med. Chem. Lett. 17(11): 3152-5.
• Suk DH, Rejman D, Dykstra CC, Pohl R, Pankiewicz KW, Patterson SE. 2007. Phosphonoxins: rational design and discovery of a potent nucleotide anti-Giardia agent. Bioorg. Med. Chem. Lett.17(10): 2811-16.
• Suk DH, Bonnac L., Dykstra CC, Pankiewicz KW, Patterson SE. 2007. Rational Design and Synthesis of Novel Nucleotide Anti-Giardia agents. Bioorg. Med. Chem. Lett. 17(10): 2811-16.
• Bonnac L, Chen L, Pathak R, Gao G, Ming Q, Bennett EM, Felczak K, Kullberg M, Patterson SE, Mazzola F, Magnia G, Pankiewicz KW. 2007. Probing binding requirements of NAD kinase with modified substrate (NAD) analogues. Bioorg Med Chem Lett 6(15): 1512-15.
• Rejman D, Olesiak M, Chen L, Patterson SE, Wilson D, Jayaram HN, Hedstrom L, Pankiewicz KW. 2006. Novel methylenephosphophosphonate analogues of mycophenolic adenine dinucleotide. Inhibition of inosine monophosphate dehydrogenase. J. Med. Chem. 49(16): 5018-22.
• Krzysztof W. Pankiewicz, Steven E. Patterson, Paul L. Black, Hiremagalur N. Jarayam, Dipesh Risal, Barry M. Goldstein, Lieven J. Stuyver, and Raymond F. Schinazi. 2004. Cofactor mimics as selective inhibitors of NAD-dependent inosine monophosphate dehydrogenase (IMPDH)--the major therapeutic target. Curr. Med. Chem. 11(7): 887-900.
• Peiyuan Wang, Laurent Hollecker, Krzysztof W. Pankiewicz, Steven E. Patterson, Tony Whitaker, Tamara R. McBrayer, Phillip M. Tharnish, Robert W. Sidwell, Lieven J. Stuyver, Michael J. Otto, Raymond F. Schinazi, and Kyoichi A. Watanabe. 2004. Synthesis of N3,5'-cyclo-4-(beta-D-ribofuranosyl)-vic-triazolo[4,5-b]pyridin-5-one, a novel compound with anti-hepatitis C virus activity. J. Med. Chem. 47(24): 6100-3.
• Lieven J. Stuyver, Tamara R. McBrayer, Phillip M. Tharnish, Abdalla E. A. Hassan, Chung K. Chu, Krzysztof W. Pankiewicz, Kyochi A. Watanabe, Raymond F. Schinazi, and Michael J. Otto. 2003. Dynamics of subgenomic hepatitis C virus replicon RNA levels in Huh-7 cells after exposure to nucleoside antimetabolites.J. Virol. 77(19): 10689-94.
• Krzysztof W. Pankiewicz and Barry M. Goldstein, Eds. 2003. Inosine Monophosphate Dehydrogenases: A Major Therapeutic Target. ACS Symposium Series No. 839.
• Lieven J. Stuyver, Stefania Lostia, Steven E. Patterson, Jeremy L. Clark, Kyoichi A. Watanabe, Michael J. Otto, and Krzysztof W. Pankiewicz. 2002. Inhibitors of the IMPDH enzyme as potential anti-bovine viral diarrhoea virus agents. Antivir. Chem. Chemother. 13(6): 345-52.