J Med Chem, 2021, 64(23):17123-17145

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

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.

Machulkin AE, Uspenskaya AA, Zyk NU, Nimenko EA, Ber AP, Petrov SA, Polshakov VI, Shafikov RR, Skvortsov DA, Plotnikova EA, Pankratov AA, Smirnova GB, Borisova YA, Pokrovsky VS, Kolmogorov VS, Vaneev AN, Khudyakov AD, Chepikova OE, Kovalev S, Zamyatnin AA, Erofeev A, Gorelkin P, Beloglazkina EK, Zyk NV, Khazanova ES, Majouga AG

IBCH: 9620
Ссылка на статью в журнале: https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01157
Кол-во цитирований на 06.2026: 31
Данные статьи проверены модераторами 2021-12-06

Список научных проектов, где отмечена публикация

  1. 20-33-70089. . Сommercial.
  2. 20-34-90150. . Сommercial.
  3. 19-14-00115. . Сommercial.
  4. 03.G25.31.0219. . Сommercial.
  5. 19-79-30062. . Сommercial.