A characteristic of prostatic epithelia that is retained during the development and progression of prostate cancer is the secretion of prostate specific antigen (PSA). This property has been exploited for diagnostic purposes. The detection of PSA in serum is a valuable tool for disease diagnosis, the monitoring of progression, and response to therapy. PSA is a serine protease produced principally by men in the prostate and is under the transcriptional regulation of the androgen receptor. It is secreted by the luminal epithelia of the prostate gland and, when mixed with seminal fluid during ejaculation, cleaves structural proteins such as the seminogelins, leading to seminal liquefaction. While much is written about the utility of PSA as a disease marker, relatively little is reported on the role the protein plays in fertility or prostate cancer pathophysiology, where cancerous tissue continues to produce high levels of active enzyme. We sought generate inhibitors of PSA’s enzymatic activity for use in answering some of the fundamental questions regarding this protein. Here, we report on the design and generation of several PSA inhibitors including beta lactam serine protease inhibitors as the template for development and modeling of the enzyme’s active site. These inhibitors display varied activity profiles against PSA and other serine proteases, with functions that affect the viability of PSA-expressing cells. These activities are consistent with what was predicted by our modeling strategy. These initial compounds provide a promising starting point for the development PSA inhibitors with high potency and selectivity for its target. These may have utility in basic and preclinical studies, and eventually the clinic.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]