A PSMA-targeted doxorubicin small-molecule drug conjugate

• Published in: Bioorganic & medicinal chemistry letters 2024-05, Vol.104, p.129712-129712, Article 129712
• Main Authors: Yoon, Hosog, Savoy, Emily A., Mesbahi, Nooshin, Hendricksen, Aaron T., March, Gabrielle L., Fulton, Melody D., Backer, Brian S., Berkman, Clifford E.
• Format: Article
• Language: English
• Subjects: Acid-labile linker; Antigens, Surface - metabolism; Cell Line, Tumor; Doxorubicin; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Drug Delivery Systems; Glutamate Carboxypeptidase II - metabolism; Humans; Male; Phosphoramidate; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; PSMA; Small molecule drug conjugate
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2024.129712

[Display omitted] We developed a model small-molecule drug conjugate (SMDC) that employed doxorubicin as a representative chemotherapeutic targeted to the cell membrane biomarker PSMA (prostate-specific membrane antigen) expressed on prostate cancer cells. The strategy capitalized on the clatherin-mediated internalization of PSMA to facilitate the selective uptake and release of doxorubicin in the target cells. The SMDC was prepared and assessed for binding kinetics, plasma stability, cell toxicity, and specificity towards PSMA expressing prostate cancer cell lines. We observed high affinity of the SMDC for PSMA (IC50 5 nM) with irreversible binding, as well as specific effectiveness against PSMA(+) cells. These findings validated the strategy for a small molecule-based approach in targeted cancer therapy.