The role of prostate-specific antigen (PSA) or kallikrein-related peptidase 3 (KLK3) as a biomarker for prostate cancer is well known; however, the precise physiological role of it's serine protease activity in prostate cancer remains a mystery. PSA is produced at high levels by both androgen-dependent and -independent prostate cancers. Studies have documented high levels of active PSA in the milieu surrounding osseous and soft tissue metastases. This evidence, coupled with growing experimental evidence, suggests that PSA plays an important role in the pathobiology of prostate cancer. These observations support the development of PSA-selective inhibitors as useful tools for the targeted treatment and imaging of prostate cancer. Here, we review the research that has been conducted to date on developing selective inhibitors for PSA. The different approaches used to determine PSA substrate specificity and for creating inhibitors are discussed. In addition, the unique active site characteristics of PSA and how these motifs aided our research in developing PSA targeted agents are highlighted.
Bibliographical noteFunding Information:
The authors would like to acknowledge Daniel Hostetter, Amanda Vlasic, and Paco Rodriguez for their careful proofreading of the manuscript and for numerous stimulating discussions related to the topic. A.M. LeBeau gratefully acknowledges the financial support of the US Department of Defense Postdoctoral Prostate Cancer Training Award PC094386.
- Human kallikrein-related peptidase 3
- Prostate cancer
- Prostate-specific antigen
- Serine protease
- Small molecule