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Prostate targeting ligands based on N-acetylated alpha-linked acidic dipeptidase
Hailun Tang1, Mark Brown, Yunpeng Ye
1Department of Biological Sciences, University of Notre Dame, Galvin Life Science Building, Notre Dame, IN 46556, USA.
Biochemical and Biophysical Research Communications
|July 10, 2003
Summary
Researchers developed novel inhibitors for prostate specific membrane antigen (PSMA) NAALADase activity. These compounds show potential for targeted prostate cancer imaging and drug delivery without significant toxicity.
Area of Science:
- Medicinal Chemistry
- Oncology
- Biochemistry
Background:
- Prostate specific membrane antigen (PSMA) possesses intrinsic N-acetylated alpha-linked acidic dipeptidase (NAALADase) activity.
- Targeting this activity could enable novel strategies for prostate cancer imaging and therapy.
Purpose of the Study:
- To synthesize and identify inhibitors of PSMA NAALADase activity.
- To evaluate these inhibitors for potential use in targeted imaging agents or chemotherapeutic drugs for prostate cancer.
Main Methods:
- Analogs of the transition state for N-acetylaspartylglutamate (NAAG) hydrolysis were synthesized.
- Inhibition assays were performed on membrane-associated enzyme from LNCaP cells.
- Cytotoxicity and cell surface binding assays were conducted.
Main Results:
- Nine compounds, including labeled conjugates, inhibited NAALADase with IC(50)s ≤ 120 nM.
- Compounds demonstrated specific and saturable binding to LNCaP cell surfaces.
- No significant alteration in cell cycle kinetics or induction of apoptosis was observed.
Conclusions:
- Identified inhibitors are potent and selective for PSMA NAALADase.
- These compounds are suitable for developing targeted imaging agents and chemotherapeutic drugs for prostate cancer.
- The lack of cytotoxicity suggests a favorable safety profile for therapeutic applications.