title: Design, synthesis and biological evaluation of PSMA/hepsin-targeted heterobivalent ligands.
abstract: Cell surface biomarkers such as prostate-specific membrane antigen (PSMA) and hepsin have received considerable attention as targets for imaging prostate cancer (PCa) due to their high cell surface expression in such tumors and easy access for imaging probes. Novel amidine-containing indole analogs (13-21) as hepsin inhibitors were designed and synthesized. These compounds showed in vitro inhibitory activity against hepsin with IC50 values from 5.9 to 70 μM. Based on the SAR of amidine-derived analogs, the novel heterobivalent compound 30, targeting both hepsin and PSMA, was synthesized by linking compound 18 with Lys-urea-Glu, the key scaffold for the specific binding to PSMA, followed by the conjugation of the optical dye SulfoCy7. Compound 30 exhibited inhibitory activities against PSMA and hepsin, with IC50 values of 28 nM and 2.8 μM, respectively. In vitro cell uptake and preliminary in vivo optical imaging studies of 30 showed selective binding and retention in both PSMA and hepsin high-expressing PC3/ML-PSMA-HPN cells as compared with low-expressing PC3/ML cells.
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea.
authors.forename: Milan
authors.initials: M
authors.lastname: Subedi
authors.affiliation: Department of Radiology, Johns Hopkins Medical Institution, 1550 Orleans street, Baltimore 21287, MD, USA.
authors.forename: Il
authors.initials: I
authors.lastname: Minn
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Chen
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea.
authors.forename: YunHye
authors.initials: Y
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea.
authors.forename: Kiwon
authors.initials: K
authors.lastname: Ok
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea.
authors.forename: Yong Woo
authors.initials: YW
authors.lastname: Jung
authors.affiliation: Department of Radiology, Johns Hopkins Medical Institution, 1550 Orleans street, Baltimore 21287, MD, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea.|Department of Radiology, Johns Hopkins Medical Institution, 1550 Orleans street, Baltimore 21287, MD, USA.|Biomedical Research Center, Korea University Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul 152-703, South Korea.
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Byun
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000954:Antigens, Surface; D007211:Indoles; D008024:Ligands; D011480:Protease Inhibitors; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D012697:Serine Endopeptidases; C055645:hepsin
keywords: Hepsin; Heterobivalent ligands; Molecular imaging; PSMA; Prostate cancer