Novel beta- and gamma-Amino Acid-Derived Inhibitors of Prostate-Specific Membrane Antigen
- Authors
- Kim, Kyul; Kwon, Hongmok; Barinka, Cyril; Motlova, Lucia; Nam, SangJin; Choi, Doyoung; Ha, Hyunsoo; Nam, Hwanhee; Son, Sang-Hyun; Minn, Il; Pomper, Martin G.; Yang, Xing; Kutil, Zsofia; Byun, Youngjoo
- Issue Date
- 26-3월-2020
- Publisher
- AMER CHEMICAL SOC
- Citation
- JOURNAL OF MEDICINAL CHEMISTRY, v.63, no.6, pp.3261 - 3273
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF MEDICINAL CHEMISTRY
- Volume
- 63
- Number
- 6
- Start Page
- 3261
- End Page
- 3273
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/57219
- DOI
- 10.1021/acs.jmedchem.9b02022
- ISSN
- 0022-2623
- Abstract
- 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 alpha-(L)-amino acids. In this study, we aimed to determine the effect of beta- and gamma-amino acids in the S1 pocket on the binding affinity for PSMA. We synthesized and evaluated the beta- and gamma-amino acid analogues with (S)- or (R)-configuration with keeping alpha-(L)-Glu as the S1'-binding pharmacophore. The structure-activity relationship studies identified that compound 13c, a beta-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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