Synthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin E Conjugate

• Published in: Journal of medicinal chemistry Vol. 64; no. 23; pp. 17123 - 17145
• Main Authors: Machulkin, Aleksei E, Uspenskaya, Anastasia A, Zyk, Nikolay U, Nimenko, Ekaterina A, Ber, Anton P, Petrov, Stanislav A, Polshakov, Vladimir I, Shafikov, Radik R, Skvortsov, Dmitry A, Plotnikova, Ekaterina A, Pankratov, Andrei A, Smirnova, Galina B, Borisova, Yulia A, Pokrovsky, Vadim S, Kolmogorov, Vasilii S, Vaneev, Alexander N, Khudyakov, Alexander D, Chepikova, Olga E, Kovalev, Sergey, Zamyatnin Jr, Andrey A, Erofeev, Alexander, Gorelkin, Petr, Beloglazkina, Elena K, Zyk, Nikolay V, Khazanova, Elena S, Majouga, Alexander G
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 09-12-2021
• Subjects: Antigens, Surface - chemistry; Cell Line, Tumor; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Glutamate Carboxypeptidase II - chemistry; Humans; Male; Microsomes, Liver - enzymology; Microsomes, Liver - metabolism; Oligopeptides - chemistry; Prostatic Neoplasms - pathology; Reactive Oxygen Species - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01157

Prostate cancer is the second most common type of cancer among men. Its main method of treatment is chemotherapy, which has a wide range of side effects. One of the solutions to this challenge is targeted delivery to prostate cancer cells. Here we synthesized a novel small-molecule PSMA-targeted conjugate based on the monomethyl auristatin E. Its structure and conformational properties were investigated by NMR spectroscopy. Cytotoxicity, intracellular reactive oxygen species induction, and stability under liver microsomes and P450-cytochrome species were investigated for this conjugate. The conjugate demonstrated 77–85% tumor growth inhibition levels on 22Rv1 (PSMA (+)) xenografts, compared with a 37% inhibition level on PC-3 (PSMA (−)) xenografts, in a single dose of 0.3 mg/kg and a sufficiently high therapeutic index of 21. Acute, chronic, and subchronic toxicities and pharmacokinetics have shown that the synthesized conjugate is a promising potential agent for the chemotherapy of prostate cancer.