Novel small molecule inhibitors for prostate-specific antigen.
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 IC50-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.
Koistinen
Hannu
H
Department of Clinical Chemistry, Biomedicum Helsinki, University of Helsinki, Helsinki University Central Hospital, Finland. hannu.k.koistinen@helsinki.fi
Wohlfahrt
Gerd
G
Mattsson
Johanna M
JM
Wu
Ping
P
Lahdenperä
Juhani
J
Stenman
Ulf-Håkan
UH
D048588:Benzoxazines / Q000737:chemistry* / Q000494:pharmacology*; D002478:Cells, Cultured; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000166:cytology; D006801:Humans; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors* / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014471:Umbilical Veins / Q000166:cytology
D048588:Benzoxazines; D054852:Small Molecule Libraries; D017430:Prostate-Specific Antigen