Synthesis and Preclinical Evaluation of Small-Molecule Prostate-Specific Membrane Antigen-Targeted Abiraterone Conjugate

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 24; p. 8795
• Main Authors: Machulkin, Aleksei E., Nimenko, Ekaterina A., Zyk, Nikolay U., Uspenskaia, Anastasiia A., Smirnova, Galina B., Khan, Irina I., Pokrovsky, Vadim S., Vaneev, Alexander N., Timoshenko, Roman V., Mamed-Nabizade, Vugara V., Zavertkina, Maria V., Erofeev, Alexander, Gorelkin, Petr, Majouga, Alexander G., Zyk, Nikolay V., Khazanova, Elena S., Beloglazkina, Elena K.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.12.2022; MDPI
• Subjects: abiraterone; Adrenal glands; Androgen Antagonists; Androgens; Androstenes - pharmacology; Antibody-drug conjugates; Antigens; Antigens, Surface; Apoptosis; Cancer therapies; Chemotherapy; Cytochrome; Cytotoxicity; drug delivery; Drug therapy; Enzymes; Fibroblasts; Health aspects; Humans; Ligands; Male; Pharmaceuticals; Production processes; Prostate - pathology; Prostate cancer; Prostate-specific antigen; prostate-specific membrane antigen; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Reactive oxygen species; Toxicity; Tumors; Russia; United States > US; prostate cancer; abiraterone; drug delivery; prostate-specific membrane antigen
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27248795

Prostate cancer is the second most common type of cancer among men. The main method of its treatment is androgen deprivation therapy, which has a wide range of side effects. One of the solutions to this challenge is the targeted delivery of drugs to prostate cancer cells. In this study, we performed the synthesis of a novel small-molecule PSMA-targeted conjugate based on abiraterone. Cytotoxicity, the induction of intracellular reactive oxygen species, and P450-cytochrome species inhibition were investigated for this conjugate PSMA-abiraterone. The conjugate demonstrated a preferential effect on prostate tumor cells, remaining inactive at up to 100 µM in human fibroblast cells. In addition, it revealed preferential efficacy, specifically on PSMA-expressing lines with a 65% tumor growth inhibition level on 22Rv1 (PSMA+) xenografts after 14-fold oral administration of PSMA-Abi at a single dose of 500 mg/kg (7.0 g/kg total dose) was observed. This compound showed significantly reduced acute toxicity with comparable efficacy compared to AbiAc.