Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 11, Pages 4224-4235Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm301718c
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Funding
- Department of Defense Prostate Cancer Training Award [W81XWH-10-1-0420]
- NCI Prostate SPORE Award [2P50CA58236]
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Prostate-specific antigen (PSA) is a serine protease produced at high levels by normal and malignant prostate epithelial cells that is used extensively as a biomarker in the clinical management of prostate cancer. To better understand PSA's role in prostate cancer progression, we prepared a library of peptidyl boronic acid-based inhibitors. To enhance selectivity for PSA vs other serine proteases, we modified the P1 site of the inhibitors to incorporate a bromopropylglycine group. This allowed the inhibitors to participate in halogen bond formation with the serine found at the bottom of the specificity pocket. The best of these Ahx-FSQn(boro)Bpg had PSA K-i of 72 nM and chymotrypsin K-i of 580 nM. In vivo studies using PSA-producing xenografts demonstrated that candidate inhibitors had minimal effect on growth but significantly altered serum levels of PSA. Biodistribution of I-125 labeled peptides showed low levels of uptake into tumors compared to other normal tissues.
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