Prostate-specific membrane antigen (PSMA) is an excellent biomarker for the early diagnosis of prostate cancer progression and metastasis. The most promising PSMA-targeted agents in the clinical phase are based on the Lys-urea-Glu motif, in which Lys and Glu are α-(l)-amino acids. In this study, we aimed to determine the effect of β- and γ-amino acids in the S1 pocket on the binding affinity for PSMA. We synthesized and evaluated the β- and γ-amino acid analogues with (S)- or (R)-configuration with keeping α-(l)-Glu as the S1'-binding pharmacophore. The structure-activity relationship studies identified that compound 13c, a β-amino acid analogue with (R)-configuration, exhibited the most potent PSMA inhibitory activity with an IC50 value of 3.97 nM. The X-ray crystal structure of PSMA in complex with 13c provided a mechanistic basis for the stereochemical preference of PSMA, which can guide the development of future PSMA inhibitors.

Biomedical Research Center Korea University Guro Hospital 148 Gurodong ro Guro gu Seoul 08308 Republic of Korea

College of Pharmacy Korea University 2511 Sejong ro Jochiwon eup Sejong 30019 Republic of Korea

Department of Nuclear Medicine Peking University 1st Hospital Beijing 100034 China

Institute of Biotechnology of the Czech Academy of Sciences BIOCEV Prumyslova 595 252 50 Vestec Czech Republic

Russell H Morgan Department of Radiology and Radiological Science Johns Hopkins University School of Medicine Baltimore 21205 Maryland United States

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