Synthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin E Conjugate
- Aleksei E. Machulkin*Aleksei E. Machulkin*Email: [email protected]Chemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian FederationMore by Aleksei E. Machulkin
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- Anastasia A. UspenskayaAnastasia A. UspenskayaChemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian FederationMore by Anastasia A. Uspenskaya
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- Nikolay U. ZykNikolay U. ZykChemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian FederationMore by Nikolay U. Zyk
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- Ekaterina A. NimenkoEkaterina A. NimenkoChemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian FederationMore by Ekaterina A. Nimenko
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- Anton P. BerAnton P. BerChemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian FederationMore by Anton P. Ber
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- Stanislav A. PetrovStanislav A. PetrovChemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian FederationMore by Stanislav A. Petrov
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- Vladimir I. PolshakovVladimir I. PolshakovCenter for Magnetic Tomography and Spectroscopy, Faculty of Fundamental Medicine, Lomonosov Moscow State University, GSP-1, Leninskie Gory, Moscow 119991, Russian FederationMore by Vladimir I. Polshakov
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- Radik R. ShafikovRadik R. ShafikovChemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian FederationShemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, GSP-7, Ulitsa Miklukho-Maklaya, 16/10, Moscow 117997, Russian FederationMore by Radik R. Shafikov
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- Dmitry A. SkvortsovDmitry A. SkvortsovChemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian FederationMore by Dmitry A. Skvortsov
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- Ekaterina A. PlotnikovaEkaterina A. PlotnikovaNational Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 2 Botkinskiy Proezd, 3, Moscow 125284, Russian FederationMore by Ekaterina A. Plotnikova
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- Andrei A. PankratovAndrei A. PankratovNational Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 2 Botkinskiy Proezd, 3, Moscow 125284, Russian FederationMore by Andrei A. Pankratov
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- Galina B. SmirnovaGalina B. SmirnovaN.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye Shosse, Moscow 115478, Russian FederationMore by Galina B. Smirnova
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- Yulia A. BorisovaYulia A. BorisovaN.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye Shosse, Moscow 115478, Russian FederationMore by Yulia A. Borisova
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- Vadim S. PokrovskyVadim S. PokrovskyN.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye Shosse, Moscow 115478, Russian FederationRUDN University, Miklukho-Maklaya Street 6, Moscow 117198, Russian FederationMore by Vadim S. Pokrovsky
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- Vasilii S. KolmogorovVasilii S. KolmogorovNational University of Science and Technology MISiS, 9 Leninskiy Prospekt, Moscow 119049, Russian FederationMore by Vasilii S. Kolmogorov
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- Alexander N. VaneevAlexander N. VaneevNational University of Science and Technology MISiS, 9 Leninskiy Prospekt, Moscow 119049, Russian FederationMore by Alexander N. Vaneev
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- Alexander D. KhudyakovAlexander D. KhudyakovChemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian FederationMore by Alexander D. Khudyakov
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- Olga E. ChepikovaOlga E. ChepikovaDepartment of Biotechnology, Sirius University of Science and Technology, 1 Olympic Avenue, Sochi 354340, Russian FederationMore by Olga E. Chepikova
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- Sergey KovalevSergey KovalevChemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian FederationMore by Sergey Kovalev
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- Andrey A. Zamyatnin JrAndrey A. Zamyatnin JrDepartment of Biotechnology, Sirius University of Science and Technology, 1 Olympic Avenue, Sochi 354340, Russian FederationInstitute of Molecular Medicine, Sechenov First Moscow State Medical University, Trubetskaya Street 8-2, Moscow 119991, Russian FederationBelozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, GSP-1, Leninskie Gory, Moscow 119992, Russian FederationFaculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, U.K.More by Andrey A. Zamyatnin Jr
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- Alexander ErofeevAlexander ErofeevNational University of Science and Technology MISiS, 9 Leninskiy Prospekt, Moscow 119049, Russian FederationMore by Alexander Erofeev
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- Petr GorelkinPetr GorelkinNational University of Science and Technology MISiS, 9 Leninskiy Prospekt, Moscow 119049, Russian FederationMore by Petr Gorelkin
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- Elena K. BeloglazkinaElena K. BeloglazkinaChemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian FederationMore by Elena K. Beloglazkina
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- Nikolay V. ZykNikolay V. ZykChemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian FederationMore by Nikolay V. Zyk
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- Elena S. KhazanovaElena S. KhazanovaLLC Izvarino-Pharma, v. Vnukovskoe, Vnukovskoe Shosse, Fifth km., Building 1, Moscow 108817, Russian FederationMore by Elena S. Khazanova
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- Alexander G. MajougaAlexander G. MajougaChemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian FederationNational University of Science and Technology MISiS, 9 Leninskiy Prospekt, Moscow 119049, Russian FederationDmitry Mendeleev University of Chemical Technology of Russia, Miusskaya Square 9, Moscow 125047, Russian FederationMore by Alexander G. Majouga
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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