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. Epub 2020 Mar 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemical synthesis
  • Amino Acids / chemistry*
  • Amino Acids / metabolism
  • Antigens, Surface / metabolism
  • Cell Line, Tumor
  • Glutamate Carboxypeptidase II / antagonists & inhibitors*
  • Glutamate Carboxypeptidase II / metabolism
  • Humans
  • Molecular Structure
  • Protein Binding
  • Structure-Activity Relationship
  • Urea / analogs & derivatives*
  • Urea / chemical synthesis
  • Urea / metabolism


  • Amino Acids
  • Antigens, Surface
  • Urea
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II