1. Synthesis and Preclinical Evaluation of Small-Molecule Prostate-Specific Membrane Antigen-Targeted Abiraterone Conjugate
- Author
-
Aleksei E. Machulkin, Ekaterina A. Nimenko, Nikolay U. Zyk, Anastasiia A. Uspenskaia, Galina B. Smirnova, Irina I. Khan, Vadim S. Pokrovsky, Alexander N. Vaneev, Roman V. Timoshenko, Vugara V. Mamed-Nabizade, Maria V. Zavertkina, Alexander Erofeev, Petr Gorelkin, Alexander G. Majouga, Nikolay V. Zyk, Elena S. Khazanova, and Elena K. Beloglazkina
- Subjects
Male ,Organic Chemistry ,Prostate ,Pharmaceutical Science ,Prostatic Neoplasms ,Androgen Antagonists ,Analytical Chemistry ,Chemistry (miscellaneous) ,Drug Discovery ,Antigens, Surface ,Molecular Medicine ,Humans ,prostate cancer ,abiraterone ,drug delivery ,prostate-specific membrane antigen ,Androstenes ,Physical and Theoretical Chemistry - Abstract
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.
- Published
- 2022