2. Academic Validation
  3. Novel β- and γ-Amino Acid-Derived Inhibitors of Prostate-Specific Membrane Antigen

Novel β- and γ-Amino Acid-Derived Inhibitors of Prostate-Specific Membrane Antigen

  • J Med Chem. 2020 Mar 26;63(6):3261-3273. doi: 10.1021/acs.jmedchem.9b02022.
Kyul Kim 1,  Hongmok Kwon 1,  Cyril Barinka 2,  Lucia Motlova 2,  SangJin Nam 1,  Doyoung Choi 1,  Hyunsoo Ha 1,  Hwanhee Nam 3,  Sang-Hyun Son 1,  Il Minn 3,  Martin G Pomper 3,  Xing Yang 4,  Zsofia Kutil 2,  Youngjoo Byun 1 5
Affiliations

Affiliations

  • 1 College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 30019, Republic of Korea.
  • 2 Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic.
  • 3 Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, 21205 Maryland, United States.
  • 4 Department of Nuclear Medicine, Peking University First Hospital, Beijing 100034 China.
  • 5 Biomedical Research Center, Korea University Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea.
PMID: 32097010 DOI: 10.1021/acs.jmedchem.9b02022
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 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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