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

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 βand γ-amino acids in the S1 pocket on the binding affinity for PSMA. We synthesized and evaluated the βand 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 IC 50 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.

PSMA-Targeting Radiopharmaceuticals for Prostate Cancer Therapy: Recent Developments and Future Perspectives

“…Cancers 2021, 13, x FOR PEER REVIEW 7 of 31 negative impacts on affinity towards PSMA when employing β-and γ-amino acids compared to the α-amino acid counterparts [68]. Similar negative effects were observed by Kwon et al by inverting the configuration of the α-amino acid in the binding region of the moiety [69].…”

“…Thereafter, the development of the Glu-urea-Lys (EUK) entity introduced a third subgroup of urea-based inhibitors (Figure 2) [66,67]. EUK-based inhibitors have thus far been the base for the most successful PSMA-targeting LMW inhibitors, such as 18 F-DCFPyL or the FDA-approved, 68 Ga-labelled PSMA-11 for PET imaging or the theranostic variants PSMA-617 and PSMA I&T. Moreover, scientists recently explored further modifications in this PSMA-binding moiety. For example, Kim et al demonstrated the negative impacts on affinity towards PSMA when employing βand γ-amino acids compared to the α-amino acid counterparts [68].…”

“…EUK-based inhibitors have thus far been the base for the most successful PSMA-targeting LMW inhibitors, such as 18 F-DCFPyL or the FDA-approved, 68 Ga-labelled PSMA-11 for PET imaging or the theranostic variants PSMA-617 and PSMA I&T. Moreover, scientists recently explored further modifications in this PSMA-binding moiety. For example, Kim et al demonstrated the negative impacts on affinity towards PSMA when employing βand γ-amino acids compared to the α-amino acid counterparts [68]. Similar negative effects were observed by Kwon et al by inverting the configuration of the α-amino acid in the binding region of the moiety [69].…”

“…In other studies based on PSMA-617, 68 Ga-labeled derivatives did not show significant improvements when the 2Nal moiety was substituted by 2-indanylglycine (Igl) or 3,3diphenylalanine (Dip) [96]. Additionally, Wüstemann et al studied the effects of different chelators on the pharmacological profile while maintaining the core structure of PSMA-617 [97].…”

“…Moreover, theranostics represent a promising approach in the field of nuclear medicine, referring to compounds that can be used for both therapy and imaging [8]. Some radiopharmaceuticals (e.g., are typical examples, as they can be complexed with positron-emitters (e.g., 68 Ga, 44 Sc or 152 Tb) for imaging and with the beta minus (β -) 177 Lu or alpha (α) 225 Ac-emitters for the treatment of the previously staged lesions [9][10][11]. As a consequence, theranostic compounds facilitate clinical applications and allow for personalised and precise treatment.…”