1. Academic Validation
  2. Design and Characterization of Squaramic Acid-Based Prostate-Specific Membrane Antigen Inhibitors for Prostate Cancer

Design and Characterization of Squaramic Acid-Based Prostate-Specific Membrane Antigen Inhibitors for Prostate Cancer

  • J Med Chem. 2023 May 25;66(10):6889-6904. doi: 10.1021/acs.jmedchem.3c00309.
Xinlin Wang 1 Yimin Chen 1 Yuqing Xiong 2 Longfei Zhang 1 Beibei Wang 2 Yajun Liu 2 Mengchao Cui 1 2
Affiliations

Affiliations

  • 1 Key Laboratory of Radiopharmaceuticals, Ministry of Education, Beijing Normal University, Beijing 100875, China.
  • 2 Center for Advanced Materials Research, Beijing Normal University at Zhuhai, Zhuhai 519087, China.
Abstract

Prostate-specific membrane antigen (PSMA) overexpressed on prostate Cancer (PCa) cells is a satisfactory theranostic target in PCa. To seek novel non-glutamate-urea-based PSMA inhibitors by the strategy of bioisosterism, 10 ligands were designed, synthesized, and characterized. Among them, ligands 17, 18, and 21-24 bearing the squaramic acid moiety proved to be potent PSMA inhibitors, with Ki values ranging from 0.40 to 2.49 nM, which are comparable or higher in inhibitory potency compared to previously reported glutamate-urea-based inhibitors. Docking studies of 15, 17, and 19 were carried out to explore their binding mode in the active site of PSMA. Two near-infrared (NIR) probes, 23EM = 650 nm) and 24EM = 1088 nm), displayed favorable in vivo NIR imaging and successful NIR-II image-guided tumor resection surgery in PSMA-positive tumor-bearing mice, which demonstrated the effectiveness of these new squaramic acid-based inhibitors.

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