Evolution of Peptide-Based Prostate-Specific Membrane Antigen (PSMA) Inhibitors: An Approach to Novel Prostate Cancer Therapeutics

Abstract

Background: Prostate cancer is one of the most common cancers worldwide, with approximately 1.1 million cases diagnosed annually. The rapid development of molecular imaging has facilitated greater structural understanding which can help formulate novel combination therapeutic regimens and more accurate diagnosis avoiding unnecessary prostate biopsies. This accumulated knowledge also provides greater understanding into aggressive stages of the disease and tumour recurrence. Recently, much progress has been made on developing peptidomimetic-based inhibitors as promising candidates to effectively bind to the prostate-specific membrane antigen (PSMA) which is expressed by prostate cancer cells. Objective: In this review, recent advances covering small-molecule and peptide-based PSMA inhibitors will be extensively reviewed, providing a base for the rational design of future PSMA inhibitors. Method: Herein, the literature on selected PSMA inhibitors that have been developed from 1996 to 2020 were reviewed, emphasizing recent synthetic advances and chemical strategies whilst highlighting therapeutic potential and drawbacks of each inhibitor. Results: Synthesized inhibitors presented in this review demonstrate the clinical application of certain PSMA inhibitors, exhibited in vitro and in vivo. Conclusion: This review highlights the clinical potential of PSMA inhibitors, analyzing the advantages and setbacks of the chemical synthetic methodologies utilized, setting precedence for the discovery of novel PSMA inhibitors for future clinical applications.