Novel β- and γ-Amino Acid-Derived Inhibitors of Prostate-Specific Membrane Antigen
| Autor: | Hongmok Kwon, Lucia Motlova, Hyunsoo Ha, Youngjoo Byun, Hwanhee Nam, K.A. Kim, Il Minn, Nam Sangjin, Xing Yang, Doyoung Choi, Martin G. Pomper, Sang Hyun Son, Zsofia Kutil, Cyril Barinka |
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| Rok vydání: | 2020 |
| Předmět: |
Glutamate Carboxypeptidase II
Plasma protein binding urologic and male genital diseases 01 natural sciences 03 medical and health sciences Prostate cancer Structure-Activity Relationship Antigen Cell Line Tumor Drug Discovery Glutamate carboxypeptidase II medicine Structure–activity relationship Humans Urea Amino Acids IC50 030304 developmental biology chemistry.chemical_classification 0303 health sciences Molecular Structure Chemistry medicine.disease 0104 chemical sciences Amino acid 010404 medicinal & biomolecular chemistry Biochemistry Antigens Surface Molecular Medicine Pharmacophore Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 63(6) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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