How a Medicinal Chemistry Project Changed the Way Prostate Cancer is Diagnosed and Treated

Area of Science:

• Oncology
• Radiopharmaceutical Chemistry
• Drug Development

Background:

• Prostate-specific membrane antigen (PSMA), also known as GCPII, is a key target in prostate cancer.
• Early research focused on neurotransmitter analogs and phosphonic acid derivatives for PSMA inhibition.

Purpose of the Study:

• To highlight the development of PSMA-targeted urea-based ligands.
• To showcase the clinical success of PSMA-targeted radiopharmaceuticals.
• To explore ongoing innovations in PSMA-targeted theranostics.

Main Methods:

• Rational drug design starting from NAAG and phosphonic acid derivatives.
• Evolution to simplified Glu-urea scaffolds with high inhibitory activity.
• Development of diagnostic and therapeutic radioligands and small molecule drug conjugates (SMDCs).

Main Results:

• Successful clinical application of radiopharmaceuticals Pylarify and Pluvicto for prostate cancer.
• Creation of effective diagnostic and therapeutic PSMA-targeting agents.
• Emergence of novel SMDCs and bifunctional targeting strategies.

Conclusions:

• PSMA-targeted urea-based ligands have transformed prostate cancer imaging and therapy.
• Collaborative chemistry and biology efforts have redefined cancer theranostics.
• Future directions include alternative binding motifs and brain-penetrant inhibitors.