Glyoxalase I inhibitors in cancer chemotherapy.
Several recent developments suggest that the GSH-dependent glyoxalase enzyme system deserves renewed interest as a potential target for antitumour drug development. This summary focuses on the design and development of new classes of tumoricidal agents that specifically target this elementary detoxification pathway in order to induce elevated concentrations of cytotoxic methylglyoxal in tumour cells. Special emphasis is placed on structure- and mechanism-based inhibitors of GlxI (glyoxalase I), the first enzyme in the pathway. A new class of bivalent transition-state analogues is described that simultaneously bind the active site on each subunit of the homodimeric human GlxI, resulting in K (i) values as low as 1 nM. Also described is a new family of bromoacyl esters of GSH that function as active-site-directed irreversible inhibitors of GlxI. Newer prodrugs for delivering the GSH-based inhibitors into tumour cells include reactive sulphoxide esters that undergo acyl exchange with endogenous GSH to give the inhibitors, and polymethacrylamide esters of the inhibitors that are potentially tumour-selective on the basis of the "enhanced permeability and retention effect". Finally, a preliminary evaluation of the efficacy of selected GlxI inhibitors in tumour-bearing mice is given.
Creighton
D J
DJ
Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, MD, U.S.A. creighto@umbc.edu
Zheng
Z-B
ZB
Holewinski
R
R
Hamilton
D S
DS
Eiseman
J L
JL
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011355:Prodrugs; D007791:Lactoylglutathione Lyase