title: Prostate targeting ligands based on N-acetylated alpha-linked acidic dipeptidase.
abstract: 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.
authors.affiliation: Department of Biological Sciences, University of Notre Dame, Galvin Life Science Building, Notre Dame, IN 46556, USA.
authors.forename: Hailun
authors.initials: H
authors.lastname: Tang
authors.forename: Mark
authors.initials: M
authors.lastname: Brown
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Ye
authors.forename: Guofeng
authors.initials: G
authors.lastname: Huang
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Wang
authors.forename: Haixiao
authors.initials: H
authors.lastname: Zhai
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Chen
authors.forename: Tsung Ying
authors.initials: TY
authors.lastname: Shen
authors.forename: Martin
authors.initials: M
authors.lastname: Tenniswood
mesh_terms: 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
chemical_list: 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