Structure-Activity Relationships of 2′,5′-Oligoadenylate Analogue Modifications of Prostate-Specific Membrane Antigen (PSMA) Antagonists

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.

Keywords:

• PSMA
• 2′, 5′-oligoadenylate conjugate
• structure-activity relationship

Acknowledgments

This work was supported by grants from Department of Defense (DOD) (W81XWH-07-1-0656, PI: W. D. W. Heston; W81XWH-05-1-0600, PI: X. Wang), and in part by grant NIH/NCI U24 CA110943 (PI: J. Duerk). The authors also thank Dr. Steve Shin-lin Huang at Cleveland Clinic for help with the manuscript.