Research Program: Carcinogenesis & Chemoprevention

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

panki001@umn.edu
612-625-7968 - office
612-625-3264 - lab
Preferred method of contact: e-mail

Dr. Pankiewicz received his Ph.D. in Medicinal Chemistry in 1979 from the Center of Molecular and Macromolecular Studies of the Polish Academy of Sciences. He completed postdoctoral training in the laboratory of Dr. Jack J. Fox and Dr. Kyoichi A. Watanabe at the Memorial Sloan-Kettering Cancer Center (MSCC) and served as an assistant and associate member at the MSCC for 15 years. He then worked as a director of Chemical Research at Pharmasset, Inc. He joined the Center for Drug Design, University of Minnesota in 2004, where his research focuses on inhibitors of NAD-dependent enzymes as potential antileukemic drugs and novel antibiotics.

Research Interests

Inhibitors of IMP-dehydrogenase for treatment of leukemias or endothelial cells cancers

Leukemic cells, as well as B- and T-cells of the human immune system, require IMP-dehydrogenase (IMPDH) for their uncontrolled growth and overexpress the type II isoform of the enzyme. Therefore, selective inhibitors of the type II isoform are of therapeutic interest as potential antileukemic drug candidates or immunosuppressants. On the other hand, the type I isoform of IMPDH was found to play a crucial role in endothelial cells, and its inhibition results in suppressing of tumor-induced angiogenesis in vitro and in vivo. Thus, the type I selective inhibitors may be valuable for treatment of tumors of endothelial tissues without affecting the immune system.

Nicotinamide adenine dinucleotide (NAD), a small molecule cofactor, is crucial for IMPDH catalytic activity. We synthesized a number of cofactor analogues that bind at the IMP-dehydrogenase but cannot participate in the enzymatic activity, resulting in potent inhibition of the enzyme. Our mycophenolic adenine dinucleotide (MAD) analogue showed no toxicity and potent anti-leukemic activity in vitro and in a SCID mouse model of chronic myelogeneous leukemia. In collaboration with Dr. Barry Goldstein, we solved the crystal structure of the complex of IMP-MAD-IMPDH and found differences between the type I and type II isoforms at the cofactor binding domain. We now exploit these differences in structure-based design of the MAD analogue(s) that would be highly selective against the type I or the type II isoform of IMPDH.

Selected Publications

Rejman D, Olesiak M, Chen L, Patterson SE, Wilson D, Jayaram HN, Hedstrom L, Pankiewicz KW. Novel Methylenephosphophosphonate Analogues of Mycophenolic Adenine Dinucleotide. Inhibition of Inosine Monophosphate Dehydrogenase. J. Med. Chem., 2006, 49, 5018-5022.

Pankiewicz KW, Patterson SE, Black PL, Jayaram HN, Risal D, Goldstein BM, Stuyver LJ, Schinazi RF., Cofactor Mimics as Selective Inhibitors of NAD-dependent Inosine Monophosphate Dehydrogenase (IMPDH) Curr. Med. Chem., 2004, 11, 887-900

Patterson SE, Black PL, Clark JL, Risal D, Goldstein BM, Jayaram HN, Schinazi RF, Pankiewicz KW. The mechanism of action and antileukemic activity of bis(phosphonate) analogue of mycophenolic adenine dinucleotide (C2-MAD); An alternative for tiazofurin? Developments in Nucleic Acids, Schinazi RF, Liotta D. eds. IHL Press, 2004, p.447-456.

Pankiewicz KW, Patterson SE, Jayaram, HN, Goldstein. Cofactor analogues as inhibitors of IMP dehydrogenase; design and new synthetic approaches. Inosine Monophosphate Dehydrogenase A Major Therapeutic Target, Pankiewicz KW, Goldstein BM Eds., ACS Symposium Series No. 839, 2003, p.247-282.