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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Prostate-specific antigen (PSA or KLK3) exhibits dual roles, inhibiting angiogenesis while potentially promoting tumor growth.
  • Modulating PSA activity presents a therapeutic strategy for prostate cancer.
  • Previous efforts identified PSA-stimulating peptides, but drug-like compounds are sought.

Purpose of the Study:

  • To screen a chemical library for drug-like compounds that modulate prostate-specific antigen (PSA) activity.
  • To identify inhibitors of PSA's proteolytic function.

Main Methods:

  • High-throughput screening of approximately 50,000 compounds for PSA activity modulation using a fluorescent substrate.
  • Assessing the anti-angiogenic effects of active compounds using a human umbilical vein endothelial cell (HUVEC) tube formation assay.

Main Results:

  • Two initial PSA inhibitors were identified, leading to structure-activity relationship studies.
  • Several compounds demonstrated micromolar IC50 values but lacked complete specificity, inhibiting related proteases like chymotrypsin.
  • Structural modifications improved PSA selectivity, and these compounds inhibited PSA's anti-angiogenic activity in the HUVEC model, confirming the role of proteolytic activity.

Conclusions:

  • Several selective PSA inhibitors were discovered.
  • These inhibitors can serve as valuable research tools for investigating PSA's function in cancer and physiological processes, particularly its role in angiogenesis.