Prodrugs Targeting Prostate-Specific Membrane Antigen against Prostate Cancer

Prostate-specific membrane antigen (PSMA) or glutamate carboxypeptidase II (GCPII) is a promising target for metastatic castration-resistant prostate cancer (mCRPC) due to its high expression in prostate cancer cell membranes and low expression in normal tissues. Ligand-targeted drugs (LTDs) targeting PSMA are gaining popularity for their high affinity, specificity, and ease of synthesis. LTDs consist of a small molecule targeting PSMA and carrying the cytotoxic agent to the cancer cells, which is then released through a cleavable linker (enzymatically or chemically cleaved) into the tumor tissue. Several PSMA-targeting LTDs have demonstrated promising results in both in vitro and in vivo studies, and a few are in clinical trials, showing potential to outperform the unmodified cytotoxic drugs. This article focuses on their structures and preclinical studies while discussing clinical data for a few very promising PSMA-targeting LTDs in detail.