Journal of Medicinal Chemistry, volume 64, issue 23, pages 17123-17145

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

Machulkin Aleksei E. ¹

Uspenskaya Anastasia A. ¹

Zyk Nikolay U ¹

Nimenko Ekaterina A. ¹

Ber Anton P ¹

Petrov Stanislav B. ¹

Polshakov Vladimir I. ²

Shafikov Radik R ^{1, 3}

Skvortsov Dmitry ¹

Plotnikova Ekaterina A ⁴

Pankratov Andrei A ⁴

Smirnova Galina B. ⁵

Borisova Yulia A. ⁵

Pokrovsky Vadim S. ^{5, 6}

Kolmogorov Vasilii S ⁷

Vaneev Alexander N. ⁷

Khudyakov Alexander D ¹

Chepikova Olga E. ⁸

Kovalev Sergey ¹

Zamyatnin A. A. ^{8, 9, 10, 11}

Erofeev Alexander V. ⁷

Gorelkin Peter ⁷

Beloglazkina Elena K. ¹

Zyk Nikolay V. ¹

Khazanova Elena S ¹²

Majouga Alexander G. ^{1, 7, 13}

Hide authors affiliations Show authors affiliations: 13 affiliations

Chemistry Department, Lomonosov Moscow State University, Building 1/3, GSP-1, Leninskie Gory, Moscow 119991, Russian Federation |

Center for Magnetic Tomography and Spectroscopy, Faculty of Fundamental Medicine, Lomonosov Moscow State University, GSP-1, Leninskie Gory, Moscow 119991, Russian Federation |

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 |

Publication type: Journal Article

Publication date: 2021-11-19

American Chemical Society (ACS)

Journal: Journal of Medicinal Chemistry

Quartile SCImago

Quartile WOS

Impact factor: 7.3

ISSN: 00222623, 15204804

DOI: 10.1021/acs.jmedchem.1c01157

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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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Citations by journals

	1 2 3
International Journal of Molecular Sciences	International Journal of Molecular Sciences, 3, 25% International Journal of Molecular Sciences 3 publications, 25%
Medicinal Chemistry Research	Medicinal Chemistry Research, 1, 8.33% Medicinal Chemistry Research 1 publication, 8.33%
Molecules	Molecules, 1, 8.33% Molecules 1 publication, 8.33%
Marine Drugs	Marine Drugs, 1, 8.33% Marine Drugs 1 publication, 8.33%
Mendeleev Communications	Mendeleev Communications, 1, 8.33% Mendeleev Communications 1 publication, 8.33%
Bioorganic Chemistry	Bioorganic Chemistry, 1, 8.33% Bioorganic Chemistry 1 publication, 8.33%
Cells	Cells, 1, 8.33% Cells 1 publication, 8.33%
Acta Pharmaceutica Sinica B	Acta Pharmaceutica Sinica B, 1, 8.33% Acta Pharmaceutica Sinica B 1 publication, 8.33%
Chemical and Pharmaceutical Bulletin	Chemical and Pharmaceutical Bulletin, 1, 8.33% Chemical and Pharmaceutical Bulletin 1 publication, 8.33%
	1 2 3

Citations by publishers

	1 2 3 4 5 6
Multidisciplinary Digital Publishing Institute (MDPI)	Multidisciplinary Digital Publishing Institute (MDPI), 6, 50% Multidisciplinary Digital Publishing Institute (MDPI) 6 publications, 50%
Elsevier	Elsevier, 3, 25% Elsevier 3 publications, 25%
Springer Nature	Springer Nature, 1, 8.33% Springer Nature 1 publication, 8.33%
Pharmaceutical Society of Japan	Pharmaceutical Society of Japan, 1, 8.33% Pharmaceutical Society of Japan 1 publication, 8.33%
	1 2 3 4 5 6

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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) Copy

Machulkin A. E., Uspenskaya A. A., Zyk N. U., Nimenko E. A., Ber A. P., Petrov S. B., Polshakov V. I., Shafikov R. R., Skvortsov D., 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., Erofeev A. V., 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.

RIS |

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RIS Copy

TY - JOUR

DO - 10.1021/acs.jmedchem.1c01157

UR - https://doi.org/10.1021%2Facs.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 - Nimenko, Ekaterina A.

AU - Ber, Anton P

AU - Borisova, Yulia A.

AU - Khudyakov, Alexander D

AU - Chepikova, Olga E.

AU - Khazanova, Elena S

AU - Zyk, Nikolay U

AU - Smirnova, Galina B.

AU - Kolmogorov, Vasilii S

AU - Zyk, Nikolay V.

AU - Pankratov, Andrei A

AU - Machulkin, Aleksei E.

AU - Plotnikova, Ekaterina A

AU - Kovalev, Sergey

AU - Beloglazkina, Elena K.

AU - Majouga, Alexander G.

AU - Uspenskaya, Anastasia A.

AU - Petrov, Stanislav B.

AU - Polshakov, Vladimir I.

AU - Shafikov, Radik R

AU - Skvortsov, Dmitry

AU - Pokrovsky, Vadim S.

AU - Vaneev, Alexander N.

AU - Zamyatnin, A. A.

AU - Erofeev, Alexander V.

AU - Gorelkin, Peter

PY - 2021

DA - 2021/11/19 00:00:00

PB - American Chemical Society (ACS)

SP - 17123-17145

IS - 23

VL - 64

SN - 0022-2623

SN - 1520-4804

ER -

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@article{2021_Machulkin,

author = {Ekaterina A. Nimenko and Anton P Ber and Yulia A. Borisova and Alexander D Khudyakov and Olga E. Chepikova and Elena S Khazanova and Nikolay U Zyk and Galina B. Smirnova and Vasilii S Kolmogorov and Nikolay V. Zyk and Andrei A Pankratov and Aleksei E. Machulkin and Ekaterina A Plotnikova and Sergey Kovalev and Elena K. Beloglazkina and Alexander G. Majouga and Anastasia A. Uspenskaya and Stanislav B. Petrov and Vladimir I. Polshakov and Radik R Shafikov and Dmitry Skvortsov and Vadim S. Pokrovsky and Alexander N. Vaneev and A. A. Zamyatnin and Alexander V. Erofeev and Peter Gorelkin},

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://doi.org/10.1021%2Facs.jmedchem.1c01157},

number = {23},

pages = {17123--17145},

doi = {10.1021/acs.jmedchem.1c01157}

}

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Machulkin, Aleksei 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, vol. 64, no. 23, Nov. 2021, pp. 17123-17145. https://doi.org/10.1021%2Facs.jmedchem.1c01157.

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American Chemical Society (ACS)

Journal

Journal of Medicinal Chemistry

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Quartile WOS

Impact factor

7.3

ISSN

00222623 (Print)
15204804 (Electronic)

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