Structure-activity relationships of 2',5'-oligoadenylate analogue modifications of prostate-specific membrane antigen (PSMA) antagonists

Nucleosides Nucleotides Nucleic Acids. 2012 May;31(5):432-44. doi: 10.1080/15257770.2012.671988.

Abstract

Prostate-specific membrane antigen (PSMA) is an ideal biomarker for prostate cancer. A previously reported 2-5A conjugate RBI1033 (3) showed binding affinity more than 10 times higher than the parent urea-based compound (S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido) pentanedioic acid (1). The purpose of this work is to further optimize the structure of 3 to identify highly selective ligands of PSMA. It was found that conjugates having 2-5A in their structure showed extraordinary improved binding affinity to PSMA compared with compound 1. Removal of 2-5A significantly reduced its biological activity. The results will provide a path to agents for targeted imaging and treatment of prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenine Nucleotides / chemistry*
  • Adenine Nucleotides / metabolism
  • Adenine Nucleotides / pharmacology*
  • Antigens, Surface
  • Binding, Competitive
  • Biological Transport
  • Cell Line, Tumor
  • Glutamate Carboxypeptidase II / antagonists & inhibitors*
  • Humans
  • Ligands
  • Male
  • Molecular Imaging
  • Neoplasm Metastasis
  • Oligoribonucleotides / chemistry*
  • Oligoribonucleotides / metabolism
  • Oligoribonucleotides / pharmacology*
  • Prostatic Neoplasms / pathology
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / metabolism
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Adenine Nucleotides
  • Antigens, Surface
  • Ligands
  • Oligoribonucleotides
  • Protease Inhibitors
  • 2',5'-oligoadenylate
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II