PSMA-targeted small-molecule docetaxel conjugate: Synthesis and preclinical evaluation

• Published in: European journal of medicinal chemistry Vol. 227; pp. 113936 - 113952
• Main Authors: Machulkin, Aleksei E., Uspenskaya, Anastasia A., Zyk, Nikolay Y., Nimenko, Ekaterina A., Ber, Anton P., Petrov, Stanislav A., Shafikov, Radik R., Skvortsov, Dmitry A., Smirnova, Galina B., Borisova, Yulia A., Pokrovsky, Vadim S., Kolmogorov, Vasilii S., Vaneev, Alexander N., Ivanenkov, Yan A., Khudyakov, Alexander D., Kovalev, Sergei V., Erofeev, Alexander S., Gorelkin, Petr V., Beloglazkina, Elena K., Zyk, Nikolay V., Khazanova, Elena S., Majouga, Alexander G.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.01.2022; Elsevier
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor agents; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Conjugates; Docetaxel; Docetaxel - chemical synthesis; Docetaxel - chemistry; Docetaxel - pharmacology; Dose-Response Relationship, Drug; Drug delivery; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; Male; Mice; Mice, Inbred ICR; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Pharmacology & Pharmacy; Prostate cancer; Prostate-Specific Antigen - antagonists & inhibitors; Prostate-Specific Antigen - genetics; Prostate-Specific Antigen - metabolism; Prostate-specific membrane antigen; Rabbits; Rats; Rats, Wistar; Science & Technology; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; Conjugates; DUPA; DMSO; Docetaxel; Drug delivery; DCL; K2EDTA; 2′S)-2; LC-MS; Antitumor agents; Prostate-specific membrane antigen; Prostate cancer; NAAG; PROSTATE; DESIGN; MEMBRANE ANTIGEN-EXPRESSION; CANCER CELLS; ANTIBODY; DELIVERY; IMMUNOGENICITY; THERAPY; TAXOL; CHEMISTRY
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113936

Prostate cancer is one of the most commonly diagnosed men's cancers and remains one of the leading causes of cancer death. The development of approaches to the treatment of this oncological disease is an ongoing process. In this work, we have carried out the selection of ligands for the creation of conjugates based on the drug docetaxel and synthesized a series of three docetaxel conjugates. In vitro cytotoxicity of these molecules was evaluated using the MTT assay. Based on the assay results, we selected the conjugate which showed cytotoxic potential close to unmodified docetaxel. At the same time, the molar solubility of the resulting compound increased up to 20 times in comparison with the drug itself. In vivo evaluation on 22Rv1 (PSMA+) xenograft model demonstrated a good potency of the synthesized conjugate to inhibit tumor growth: the inhibition turned out to be more than 80% at a dose of 30 mg/kg. Pharmacokinetic parameters of conjugate distribution were analyzed. Also, it was found that PSMA-targeted docetaxel conjugate is less toxic than docetaxel itself, the decrease of molar acute toxicity in comparison with free docetaxel was up to 20%. Obtained conjugate PSMA-DOC is a good candidate for further expanded preclinical trials because of high antitumor activity, fewer side toxic effects and better solubility. [Display omitted] •A series of three docetaxel PSMA-targeted conjugates were synthesized.•The most potent conjugate PSMA-DOC demonstrated IC50 value 2.7 on 22Rv1 cell line.•Tumor growth inhibition on 22Rv1 xenografts was 87% at a PSMA-DOC dosage of 10 mg/kg.•PSMA-DOC conjugate demonstrated increased solubility and decreased general toxicity.•PSMA-DOC pharmacokinetics, subchonic and chronic toxicities were estimated.