Synthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin e Conjugate
Nikolay U Zyk
1
,
Ekaterina A. Nimenko
1
,
Anton P Ber
1
,
Stanislav A Petrov
1
,
Radik R Shafikov
1, 3
,
Dmitry Skvortsov
1
,
Dmitry A. Skvortsov
1
,
Andrei A Pankratov
4
,
Galina B. Smirnova
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
,
A. A. Zamyatnin
8, 9, 10, 11
,
Andrey A. Zamyatnin Jr
8, 9, 10, 11
,
Alexander Erofeev
7
,
Peter Gorelkin
7
,
Petr Gorelkin
7
,
Nikolay V. Zyk
1
,
Elena S Khazanova
12
,
Alexander G. Majouga
1, 7, 13
12
LLC Izvarino-Pharma, v. Vnukovskoe, Vnukovskoe Shosse, Fifth km., Building 1, Moscow 108817, Russian Federation
|
Publication type: Journal Article
Publication date: 2021-11-19
scimago Q1
wos Q1
SJR: 1.801
CiteScore: 11.5
Impact factor: 6.8
ISSN: 00222623, 15204804
PubMed ID:
34797052
Drug Discovery
Molecular Medicine
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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28
Total citations:
28
Citations from 2024:
18
(64%)
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MLA
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GOST
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Machulkin A. E. et al. Synthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin e Conjugate // Journal of Medicinal Chemistry. 2021. Vol. 64. No. 23. pp. 17123-17145.
GOST all authors (up to 50)
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Machulkin A. E., Uspenskaya A. A., Zyk N. U., Nimenko E. A., Ber A. P., Petrov S. B., Petrov S. A., Polshakov V. I., Shafikov R. R., Skvortsov D., Skvortsov D. A., Plotnikova E. A., Pankratov A. A., Smirnova G. B., Borisova Y. A., Pokrovsky V. S., Kolmogorov V. S., Vaneev A. N., Khudyakov A. D., Chepikova O. E., Kovalev S., Zamyatnin A. A., Zamyatnin Jr A. A., Erofeev A. V., Erofeev A., Gorelkin P., Gorelkin P., Beloglazkina E. K., Zyk N. V., Khazanova E. S., Majouga A. G. Synthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin e Conjugate // Journal of Medicinal Chemistry. 2021. Vol. 64. No. 23. pp. 17123-17145.
Cite this
RIS
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TY - JOUR
DO - 10.1021/acs.jmedchem.1c01157
UR - https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01157
TI - Synthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin e Conjugate
T2 - Journal of Medicinal Chemistry
AU - Machulkin, Aleksei E.
AU - Uspenskaya, Anastasia A.
AU - Zyk, Nikolay U
AU - Nimenko, Ekaterina A.
AU - Ber, Anton P
AU - Petrov, Stanislav B.
AU - Petrov, Stanislav A
AU - Polshakov, Vladimir I.
AU - Shafikov, Radik R
AU - Skvortsov, Dmitry
AU - Skvortsov, Dmitry A.
AU - Plotnikova, Ekaterina A
AU - Pankratov, Andrei A
AU - Smirnova, Galina B.
AU - Borisova, Yulia A.
AU - Pokrovsky, Vadim S.
AU - Kolmogorov, Vasilii S
AU - Vaneev, Alexander N.
AU - Khudyakov, Alexander D
AU - Chepikova, Olga E.
AU - Kovalev, Sergey
AU - Zamyatnin, A. A.
AU - Zamyatnin Jr, Andrey A.
AU - Erofeev, Alexander V.
AU - Erofeev, Alexander
AU - Gorelkin, Peter
AU - Gorelkin, Petr
AU - Beloglazkina, Elena K.
AU - Zyk, Nikolay V.
AU - Khazanova, Elena S
AU - Majouga, Alexander G.
PY - 2021
DA - 2021/11/19
PB - American Chemical Society (ACS)
SP - 17123-17145
IS - 23
VL - 64
PMID - 34797052
SN - 0022-2623
SN - 1520-4804
ER -
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BibTex (up to 50 authors)
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@article{2021_Machulkin,
author = {Aleksei E. Machulkin and Anastasia A. Uspenskaya and Nikolay U Zyk and Ekaterina A. Nimenko and Anton P Ber and Stanislav B. Petrov and Stanislav A Petrov and Vladimir I. Polshakov and Radik R Shafikov and Dmitry Skvortsov and Dmitry A. Skvortsov and Ekaterina A Plotnikova and Andrei A Pankratov and Galina B. Smirnova and Yulia A. Borisova and Vadim S. Pokrovsky and Vasilii S Kolmogorov and Alexander N. Vaneev and Alexander D Khudyakov and Olga E. Chepikova and Sergey Kovalev and A. A. Zamyatnin and Andrey A. Zamyatnin Jr and Alexander V. Erofeev and Alexander Erofeev and Peter Gorelkin and Petr Gorelkin and Elena K. Beloglazkina and Nikolay V. Zyk and Elena S Khazanova and Alexander G. Majouga},
title = {Synthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin e Conjugate},
journal = {Journal of Medicinal Chemistry},
year = {2021},
volume = {64},
publisher = {American Chemical Society (ACS)},
month = {nov},
url = {https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01157},
number = {23},
pages = {17123--17145},
doi = {10.1021/acs.jmedchem.1c01157}
}
Cite this
MLA
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Machulkin, Aleksei E., et al. āSynthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin e Conjugate.ā Journal of Medicinal Chemistry, vol. 64, no. 23, Nov. 2021, pp. 17123-17145. https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01157.