Science and Research
Advances in our understanding of tumor biology have led to new approaches by preferentially targeting cancer cells based on their unique protein markers. Several prostate antigens have been identified for candidate antibody-drug conjugate (ADC) and small molecule drug conjugate (SMDC) targeting, and one of the most studied protein markers in this category is the prostate-specific membrane antigen (PSMA).
Figure 1: Prostate cancer spreads to bones and soft tissues. In this illustration, injection of a radiopharmaceutical that consists of a PSMA ligand and a radioisotope can be used to identify locations of metastatic lesions, and with the delivery of a stronger radiation dose, the lesions can be treated to result in regression, symptom relief and prolongation of life.
PSMA Ligands
Discovery and characterization of the PSMA by Gerald Murphy at Memorial Sloan Kettering in the late 1980s opened the door for PSMA-targeted diagnostics and therapeutics. In prostate cancer, the PSMA enzyme mechanisms have been shown to drive cancer growth.
In other work performed by Neale and Kozikowski at Georgetown University, an inhibitor of the GCP II, an enzyme present in the brain with a role in regulating neurotransmitter activity, led to the discovery of the first highly selective ligand based on a stable urea motif. The subsequent observation that GCP II and PSMA were the same enzyme opened the door to development of PSMA-ligand targeted radiopharmaceuticals for PET imaging and radioisotope mediated radiation treatment of prostate cancers.
Figure 2. To achieve precision medicine goals for prostate cancer, the PSMA-targeting SMDC binds to the receptors on the surfaces of prostate cancer cells and following internalization into the cell cytoplasm, the linker is cleaved to release the drug payload, here shown as a PARP inhibitor. The free inhibitor enters the nucleus to bind to PARP enzyme molecules to effect the synthetic lethality mechanism of cancer cell killing.
To explore the role of PSMA/GCP-II regulation in pain signaling (described in Figure 3), the PSMA inhibitor ZJ-43 demonstrated efficacy in controlling pain in a mouse model. Prostate Theranostics is exploring novel formulations for improving the drug candidate's penetration of the blood brain barrier for potential use in managing pain in patients with advanced prostate cancer.
Figure 3. Pain inhibition by the PSMA Inhibitor ZJ-43 through Inhibition of NAAG Hydrolysis.
Administration of the potent urea-based PSMA (GCPII) inhibitor ZJ-43 reduces pain responses in rodent models by preventing the enzymatic hydrolysis of N-acetylaspartylglutamate (NAAG) to glutamate. This figure depicts the proposed mechanism of action linking PSMA inhibition, elevated NAAG levels, and decreased excitatory neurotransmission that underlie the analgesic effect of ZJ-43.
Prostate Cancer Treatment Platform
2025 - How a Medicinal Chemistry Project Changed the Way Prostate Cancer is Diagnosed and Treated. For inquiries or more information on this important topic, feel free to contact us. Understanding health matters is crucial, and this research highlights significant advancements in cancer care.
https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c01593
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