title: Structural optimization, biological evaluation, and application of peptidomimetic prostate specific antigen inhibitors.
abstract: Prostate-specific antigen (PSA) is a serine protease produced at high levels by normal and malignant prostate epithelial cells that is used extensively as a biomarker in the clinical management of prostate cancer. To better understand PSA's role in prostate cancer progression, we prepared a library of peptidyl boronic acid-based inhibitors. To enhance selectivity for PSA vs other serine proteases, we modified the P1 site of the inhibitors to incorporate a bromopropylglycine group. This allowed the inhibitors to participate in halogen bond formation with the serine found at the bottom of the specificity pocket. The best of these Ahx-FSQn(boro)Bpg had PSA Ki of 72 nM and chymotrypsin Ki of 580 nM. In vivo studies using PSA-producing xenografts demonstrated that candidate inhibitors had minimal effect on growth but significantly altered serum levels of PSA. Biodistribution of (125)I labeled peptides showed low levels of uptake into tumors compared to other normal tissues.
authors.affiliation: Department of Oncology, The Johns Hopkins University, School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Maya B
authors.initials: MB
authors.lastname: Kostova
authors.forename: D Marc
authors.initials: DM
authors.lastname: Rosen
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Ronnie C
authors.initials: RC
authors.lastname: Mease
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Denmeade
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D001897:Boronic Acids; D007457:Iodine Radioisotopes; D057786:Peptidomimetics; D019275:Radiopharmaceuticals; D017430:Prostate-Specific Antigen