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Novel β- and γ-Amino Acid-Derived Inhibitors of Prostate-Specific Membrane Antigen
K. Kim, H. Kwon, C. Barinka, L. Motlova, S. Nam, D. Choi, H. Ha, H. Nam, SH. Son, I. Minn, MG. Pomper, X. Yang, Z. Kutil, Y. Byun,
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Amino Acids chemical synthesis chemistry metabolism MeSH
- Antigens, Surface metabolism MeSH
- Glutamate Carboxypeptidase II antagonists & inhibitors metabolism MeSH
- Humans MeSH
- Urea analogs & derivatives chemical synthesis metabolism MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Protein Binding MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
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
References provided by Crossref.org
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- $a 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.
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