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

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.

前列腺特异性膜抗原（Prostate-specific membrane antigen, PSMA）是用于前列腺癌进展与转移早期诊断的优质生物标志物。当前临床阶段最具开发前景的PSMA靶向配体，均基于赖氨酸（Lys）-脲基-谷氨酸（Glu）基序，该基序中的Lys与Glu均为α-(L)-氨基酸。本研究旨在探究S1口袋内的β-及γ-氨基酸对PSMA结合亲和力的影响。我们合成并评估了保留α-(L)-谷氨酸作为S1'结合药效团的、具有(S)-或(R)-构型的β-及γ-氨基酸类似物。构效关系研究结果显示，具有(R)-构型的β-氨基酸类似物13c展现出最强的PSMA抑制活性，其半最大抑制浓度（IC50）为3.97 nM。PSMA与13c形成复合物的X射线晶体结构，为PSMA的立体选择性偏好提供了机制层面的理论依据，该成果可为未来PSMA抑制剂的开发提供指导方向。