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

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

  • J Med Chem. 2021 Dec 9;64(23):17123-17145. doi: 10.1021/acs.jmedchem.1c01157.
Aleksei E Machulkin 1,  Anastasia A Uspenskaya 1,  Nikolay U Zyk 1,  Ekaterina A Nimenko 1,  Anton P Ber 1,  Stanislav A Petrov 1,  Vladimir I Polshakov 2,  Radik R Shafikov 1 3,  Dmitry A Skvortsov 1,  Ekaterina A Plotnikova 4,  Andrei A Pankratov 4,  Galina B Smirnova 5,  Yulia A Borisova 5,  Vadim S Pokrovsky 5 6,  Vasilii S Kolmogorov 7,  Alexander N Vaneev 7,  Alexander D Khudyakov 1,  Olga E Chepikova 8,  Sergey Kovalev 1,  Andrey A Zamyatnin Jr 8 9 10 11,  Alexander Erofeev 7,  Petr Gorelkin 7,  Elena K Beloglazkina 1,  Nikolay V Zyk 1,  Elena S Khazanova 12,  Alexander G Majouga 1 7 13
Affiliations

Affiliations

  • 1 Chemistry Department, Lomonosov Moscow State University, Building 1/3, 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 of the 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, U.K.
  • 12 LLC Izvarino-Pharma, v. Vnukovskoe, Vnukovskoe Shosse, Fifth km., Building 1, Moscow 108817, Russian Federation.
  • 13 Dmitry Mendeleev University of Chemical Technology of Russia, Miusskaya Square 9, Moscow 125047, Russian Federation.
PMID: 34797052 DOI: 10.1021/acs.jmedchem.1c01157
Abstract

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.

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