title: 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.
authors.affiliation: Department of Cancer Biology , Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Xinning
authors.initials: X
authors.lastname: Wang
authors.forename: Haibin
authors.initials: H
authors.lastname: Tian
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Lee
authors.forename: Warren D W
authors.initials: WD
authors.lastname: Heston
mesh_terms: D000227:Adenine Nucleotides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000954:Antigens, Surface; D001667:Binding, Competitive; D001692:Biological Transport; D045744:Cell Line, Tumor; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D006801:Humans; D008024:Ligands; D008297:Male; D057054:Molecular Imaging; D009362:Neoplasm Metastasis; D009843:Oligoribonucleotides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000227:Adenine Nucleotides; D000954:Antigens, Surface; D008024:Ligands; D009843:Oligoribonucleotides; D011480:Protease Inhibitors; C023505:2',5'-oligoadenylate; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II