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. © 2021 American Chemical Society.

Authors
Machulkin A.E.1 , Uspenskaya A.A.1 , Zyk N.U.1 , Nimenko E.A.1 , Ber A.P.1 , Petrov S.A.1 , Polshakov V.I.2 , Shafikov R.R.1, 3 , Skvortsov D.A.1 , Plotnikova E.A.4 , Pankratov A.A.4 , Smirnova G.B.5 , Borisova Y.A.5 , Pokrovsky V.S. 5, 6 , Kolmogorov V.S.7 , Vaneev A.N.7 , Khudyakov A.D.1 , Chepikova O.E.8 , Kovalev S.1 , Zamyatnin Jr A.A. , Erofeev A.7 , Gorelkin P.7 , Beloglazkina E.K.1 , Zyk N.V.1 , Khazanova E.S.12 , Majouga A.G.1, 7, 13
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Language
English
Status
Published
Link
External link
DOI
10.1021/acs.jmedchem.1c01157
Year
2021
Organizations
  • 1 Chemistry Department, Lomonosov Moscow State University, GSP-1, Leninskie Gory, Moscow, 119991, Russian Federation
  • 2 Center for Magnetic Tomography and Spectroscopy, Faculty of Fundamental Medicine, Lomonosov Moscow State University, GSP-1, Leninskie Gory, Moscow, 119991, Russian Federation
  • 3 Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, GSP-7, Ulitsa Miklukho-Maklaya, 16/10, Moscow, 117997, Russian Federation
  • 4 National Medical Research Radiological Centre, Ministry of Health of the Russian Federation, 2 Botkinskiy Proezd, 3, Moscow, 125284, Russian Federation
  • 5 N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye Shosse, Moscow, 115478, Russian Federation
  • 6 RUDN University, Miklukho-Maklaya Street 6, Moscow, 117198, Russian Federation
  • 7 National University of Science and Technology MISiS, 9 Leninskiy Prospekt, Moscow, 119049, Russian Federation
  • 8 Department of Biotechnology, Sirius University of Science and Technology, 1 Olympic Avenue, Sochi, 354340, Russian Federation
  • 9 Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Trubetskaya Street 8-2, Moscow, 119991, Russian Federation
  • 10 Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, GSP-1, Leninskie Gory, Moscow, 119992, Russian Federation
  • 11 Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XH, United Kingdom
  • 12 LLC Izvarino-Pharma, v. Vnukovskoe, Vnukovskoe Shosse, Fifth km., Moscow, 108817, Russian Federation
  • 13 Dmitry Mendeleev University of Chemical Technology of Russia, Miusskaya Square 9, Moscow, 125047, Russian Federation
Date of creation
16.12.2021
Date of change
16.12.2021
Short link
https://repository.rudn.ru/en/records/article/record/76847/
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