Prostate targeting ligands based on N-acetylated alpha-linked acidic dipeptidase.
To identify inhibitors of the intrinsic N-acetylated alpha-linked acidic dipeptidase (NAALADase) activity of prostate specific membrane antigen (PSMA) that may be useful for targeting imaging agents or chemotherapeutic drugs to disseminated prostate cancer, analogs of the tetrahedral transition state for hydrolysis of the natural substrate, N-acetylaspartylglutamate (NAAG), were synthesized. These compounds were assayed for their ability to inhibit the membrane-associated enzyme isolated from LNCaP prostate cancer cells. Active inhibitors were further assayed for their cytotoxicity and membrane binding. We have identified nine compounds, including fluorescent and iodine-labeled conjugates, which inhibit NAALADase enzyme activity with IC(50)s at, or below, 120nM. The binding of these compounds to the cell surface of viable LNCaP prostate tumor cells appears to be specific and saturable, and none of the compounds alter the cell cycle kinetics or induce apoptosis in LNCaP cells, suggesting that they are relatively innocuous and are suitable for targeting imaging agents or cytotoxic drugs to disseminated prostate cancer.
Tang
Hailun
H
Department of Biological Sciences, University of Notre Dame, Galvin Life Science Building, Notre Dame, IN 46556, USA.
Brown
Mark
M
Ye
Yunpeng
Y
Huang
Guofeng
G
Zhang
Yihua
Y
Wang
Yuesheng
Y
Zhai
Haixiao
H
Chen
Xiaohui
X
Shen
Tsung Ying
TY
Tenniswood
Martin
M
D000951:Antigens, Neoplasm / Q000378:metabolism; D000954:Antigens, Surface; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D004151:Dipeptides / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000378:metabolism; D043425:Glutamate Carboxypeptidase II; D006801:Humans; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D004151:Dipeptides; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D008024:Ligands; D020033:Protein Isoforms; C027172:isospaglumic acid; D002268:Carboxypeptidases; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II