Prostate targeting ligands based on N-acetylated α-linked acidic dipeptidase

To identify inhibitors of the intrinsic N-acetylated α-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 fo...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2003-07, Vol.307 (1), p.8-14
Main Authors: Tang, Hailun, Brown, Mark, Ye, Yunpeng, Huang, Guofeng, Zhang, Yihua, Wang, Yuesheng, Zhai, Haixiao, Chen, Xiaohui, Shen, Tsung Ying, Tenniswood, Martin
Format: Article
Language:English
Subjects:
Antigens, Neoplasm - metabolism
Antigens, Surface
Carboxypeptidases - antagonists & inhibitors
Carboxypeptidases - metabolism
Cell Membrane - metabolism
Cell Survival
Dipeptides - metabolism
Enzyme Inhibitors - metabolism
Fluorescent Dyes - metabolism
Glutamate carboxypeptidase
Glutamate Carboxypeptidase II
Humans
Ligands
Male
Metastasis
Molecular Structure
NAALADase
Prostate - metabolism
Prostate cancer
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Protein Isoforms - metabolism
PSMA
Tumor Cells, Cultured
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Summary:To identify inhibitors of the intrinsic N-acetylated α-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 50s at, or below, 120 nM. 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.
ISSN:0006-291X
1090-2104
DOI:10.1016/S0006-291X(03)01119-7