Krzysztof W. Pankiewicz - Research

Research Details
 
Inhibitors of IMP-dehydrogenase for treatment of Chronic Myelogenous Leukemia (CML)

Cancer cells, including CML cells, require IMP-dehydrogenase (IMPDH) for their uncontrolled growth and overexpress the type II isoform of the enzyme. The type I isoform, a "housekeeping" enzyme, is dominant in normal cells. We focus on synthesis of specific inhibitors of the type II isoform. Such compounds should show antileukemic effects without affecting normal cells that use the type I isoform.

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) analogues showed potent anti-CML activity in vitro and in a SCID mouse model but are not specific for either isoform. 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 specific or highly selective against the type II of IMPDH.

Shown on the right is the crystal structure of the Type II enzyme with C2-MAD and RMP bound, with an overlay of MPA and IMP from the structure of the hamster enzyme. The active site loop is shown in yellow. Key differences between Type I and Type II include the substitution of the three residues shown in light blue at the bottom left of the figure. In Type I IMPDH, His253 becomes Arg, Phe282 becomes Tyr, and Thr458 becomes Ile.

Isoniazid (INH), an old "first line" antibiotic against tuberculosis (TB), needs metabolic activation to form a covalent complex with NAD. This complex inhibits the enoyl-reductase, an enzyme involved in mycolic acid synthesis crucial for the growth of Mycobacterium tuberculosis. Recent studies have shown that multi-drug resistant TB strains (MDR-TB) do not activate INH to form such a complex. We are preparing NAD analogues that mimic the complex properties but do not require metabolic activation and therefore are expected to have therapeutic potential against MDR-TB.

Substantial differences between the NAD binding site of human IMPDH and IMPDH enzymes from other sources have been demonstrated. We are targeting these differences for designing inhibitors that will not affect the human enzyme. We design potential inhibitors against bacterial, fungal, and protozoan pathogens including S. pyogenes, P. carinii, C. parvum, and C. albicans.

We continue our search for inhibitors of viral RNA-dependent RNA polymerases and Flaviviridae virus replication by synthesis of nucleosides and nucleotide analogues (such as phosphonates). We are also synthesizing analogs of mycophenolic acid (MPA) as potential inhibitors of RNA virus replication. MPA is one of the most potent agents against WNV.

Representative Publications

Recent development of IMP dehydrogenase inhibitors for the treatment of cancer. Chen L, Pankiewicz, KW. Curr. Opin. Drug Discov. Devel. 2007 10(4): 403-12. Abstract

Synthesis of 4-phenoxybenzamide adenine dinucleotide as NAD analogue with inhibitory activity against enoyl-ACP reductase (InhA) of Mycobacterium tuberculosis. Bonnac L, Gao GY, Chen L, Felczak K, Bennett EM, Xu H, Kim T, Liu N, Oh H, Tonge PJ, Pankiewicz, KW. Bioorg. Med. CHem. Lett. 2007 17(17): 4588-91. Abstract

Methylenebis(sulfonamide) linked nicotinamide adenine dinucleotide analogue as an inosine monophosphate dehydrogenase inhibitor. Chen L, Gao G, Bonnac L, Wilson DJ, Bennett EM, Jayaram HN, Pankiewicz KW. Bioorg. Med. Chem. Lett. 2007 17(11): 3152-5. Abstract

Phosphonoxins: rational design and discovery of a potent nucleotide anti-Giardia agent. Suk DH, Rejman D, Dykstra CC, Pohl R, Pankiewicz KW, Patterson SE. Bioorg. Med. Chem. Lett. 2007, 17(10): 2811-16. Abstract

Rational Design and Synthesis of Novel Nucleotide Anti-Giardia agents. Suk DH, Bonnac L., Dykstra CC, Pankiewicz KW, Patterson SE. Bioorg. Med. Chem. Lett. 2007, 17(10): 2811-16. Abstract

Probing binding requirements of NAD kinase with modified substrate (NAD) analogues. Bonnac L, Chen L, Pathak R, Gao G, Ming Q, Bennett EM, Felczak K, Kullberg M, Patterson SE, Mazzola F, Magnia G, Pankiewicz KW. Bioorg Med Chem Lett 2007 6(15): 1512-15. Abstract

Novel methylenephosphophosphonate analogues of mycophenolic adenine dinucleotide. Inhibition of inosine monophosphate dehydrogenase. J. Med. Chem. 2006 49(16): 5018-22. Abstract

Cofactor mimics as selective inhibitors of NAD-dependent inosine monophosphate dehydrogenase (IMPDH)--the major therapeutic target. Krzysztof W. Pankiewicz, Steven E. Patterson, Paul L. Black, Hiremagalur N. Jarayam, Dipesh Risal, Barry M. Goldstein, Lieven J. Stuyver, and Raymond F. Schinazi. Curr. Med. Chem. 11(7): 887-900 (2004). Abstract

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. 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. J. Med. Chem. 47(24): 6100-3 (2004). Abstract

Dynamics of subgenomic hepatitis C virus replicon RNA levels in Huh-7 cells after exposure to nucleoside antimetabolites. 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. J. Virol. 77(19): 10689-94 (2003). Abstract

Inosine Monophosphate Dehydrogenases: A Major Therapeutic Target. Krzysztof W. Pankiewicz and Barry M. Goldstein, Eds. ACS Symposium Series No. 839 (2003). Abstract

Inhibitors of the IMPDH enzyme as potential anti-bovine viral diarrhoea virus agents. Lieven J. Stuyver, Stefania Lostia, Steven E. Patterson, Jeremy L. Clark, Kyoichi A. Watanabe, Michael J. Otto, and Krzysztof W. Pankiewicz. Antivir. Chem. Chemother. 13(6): 345-52 (2002). Abstract

Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia. Krzysztof W. Pankiewicz, Krystyna B. Lesiak-Watanabe, Kyoichi A. Watanabe, Steven E. Patterson, Hiremagalur N. Jayaram, Joel A. Yalowitz, Michael D. Miller, Michael Seidman, Alokes Majumdar, Gerd Prehna, and Barry M. Goldstein. J. Med. Chem. 45(3): 703-12 (2002). Abstract

The chemistry of nicotinamide adenine dinucleotide (NAD) analogues containing C-nucleosides related to nicotinamide riboside. Krzysztof W. Pankiewicz, Kyoichi A. Watanabe, Krystyna B. Lesiak-Watanabe, Barry M. Goldstein, and Hiremagalur N. Jarayam. Curr. Med. Chem., 9(7): 733-41 (2002). Abstract

Novel mycophenolic adenine bis(phosphonate)s as potent anticancer agents and inducers of cells differentiation. Krzysztof W. Pankiewicz and Krystyna Lesiak-Watanabe. Nucleosides Nucleotides 18: 927-32 (1999) Abstract

The practical synthesis of a methylenebisphosphonate analogue of benzamide adenine dinucleotide: inhibition of human inosine monophosphate dehydrogenase (type I and II). Krzysztof W. Pankiewicz, Krystyna Lesiak, Andrzej Zatorski, Barry M. Goldstein, Stephen F. Carr, Marek Sochacki, Alokes Majumdar, Michael Seidman, and Kyoichi A. Watanabe. J. Med. Chem. 1997, 40(8): 1287-91. Abstract