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Synthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin E Conjugate.
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, Andrey A; Erofeev, Alexander; Gorelkin, Petr; Beloglazkina, Elena K; Zyk, Nikolay V; Khazanova, Elena S; Majouga, Alexander G.
Affiliation
  • Machulkin AE; Chemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian Federation.
  • Uspenskaya AA; Chemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian Federation.
  • Zyk NU; Chemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian Federation.
  • Nimenko EA; Chemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian Federation.
  • Ber AP; Chemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian Federation.
  • Petrov SA; Chemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian Federation.
  • Polshakov VI; Center for Magnetic Tomography and Spectroscopy, Faculty of Fundamental Medicine, Lomonosov Moscow State University, GSP-1, Leninskie Gory, Moscow 119991, Russian Federation.
  • Shafikov RR; Chemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian Federation.
  • Skvortsov DA; Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, GSP-7, Ulitsa Miklukho-Maklaya, 16/10, Moscow 117997, Russian Federation.
  • Plotnikova EA; Chemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian Federation.
  • Pankratov AA; National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 2 Botkinskiy Proezd, 3, Moscow 125284, Russian Federation.
  • Smirnova GB; National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 2 Botkinskiy Proezd, 3, Moscow 125284, Russian Federation.
  • Borisova YA; N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye Shosse, Moscow 115478, Russian Federation.
  • Pokrovsky VS; N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye Shosse, Moscow 115478, Russian Federation.
  • Kolmogorov VS; N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye Shosse, Moscow 115478, Russian Federation.
  • Vaneev AN; RUDN University, Miklukho-Maklaya Street 6, Moscow 117198, Russian Federation.
  • Khudyakov AD; National University of Science and Technology MISiS, 9 Leninskiy Prospekt, Moscow 119049, Russian Federation.
  • Chepikova OE; National University of Science and Technology MISiS, 9 Leninskiy Prospekt, Moscow 119049, Russian Federation.
  • Kovalev S; Chemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian Federation.
  • Zamyatnin AA; Department of Biotechnology, Sirius University of Science and Technology, 1 Olympic Avenue, Sochi 354340, Russian Federation.
  • Erofeev A; Chemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian Federation.
  • Gorelkin P; Department of Biotechnology, Sirius University of Science and Technology, 1 Olympic Avenue, Sochi 354340, Russian Federation.
  • Beloglazkina EK; Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Trubetskaya Street 8-2, Moscow 119991, Russian Federation.
  • Zyk NV; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, GSP-1, Leninskie Gory, Moscow 119992, Russian Federation.
  • Khazanova ES; Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, U.K.
  • Majouga AG; National University of Science and Technology MISiS, 9 Leninskiy Prospekt, Moscow 119049, Russian Federation.
J Med Chem ; 64(23): 17123-17145, 2021 12 09.
Article in En | MEDLINE | ID: mdl-34797052
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Oligopeptides / Glutamate Carboxypeptidase II / Coordination Complexes / Antigens, Surface Limits: Humans / Male Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2021 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Oligopeptides / Glutamate Carboxypeptidase II / Coordination Complexes / Antigens, Surface Limits: Humans / Male Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2021 Document type: Article