Novel small molecule inhibitors for prostate‐specific antigen

Abstract Background Prostate‐specific antigen (PSA or KLK3) has been shown to inhibit angiogenesis, but it might also have tumor promoting activities. Thus, it may be possible to modulate prostate cancer growth by stimulating or inhibiting the activity of PSA. To this end we have previously identified peptides that stimulate the activity of PSA. As peptides have several limitations as drug molecules, we screened a chemical library to find drug‐like compounds that could be used to modulate the function(s) of PSA. Methods Almost 50,000 compounds were analyzed for their ability to modulate PSA activity towards a fluorescent PSA‐substrate. The ability of the most active compounds to affect the anti‐angiogenic activity of PSA was analyzed by human umbilical vein endothelial cell (HUVEC) tube formation assay. Results In the initial screening we identified two compounds that inhibited PSA activity. Based on these, similar compounds were selected and tested for activity to define structure–activity relationships. Several compounds with micromolar IC 50 ‐values were found, but they were not entirely specific towards PSA, e.g., they inhibited chymotrypsin, which has similar substrate specificity as PSA. However, it was possibly to improve the selectivity of the compounds towards PSA by small structural changes. These compounds inhibited the anti‐angiogenic activity of PSA in the HUVEC model, proving that the proteolytic activity of PSA is essential for inhibition of angiogenesis. Conclusions We found several PSA inhibitors that could be useful tools for studying the role of PSA in cancer models and in normal physiology as showed in angiogenesis model. Prostate 68: 1143–1151, 2008. © 2008 Wiley‐Liss, Inc.