Synthesis, characterization and preclinical evaluation of small-molecule prostate-specific membrane antigen targeted monomethyl auristatin E conjugate

Machulkin, A.E.; Uspenskaya, A.A.; Zyk, N.U.; Nimenko, E.A.; Ber, A.P.; Petrov, S.A.; Polshakov, V.I.; Shafikov, R.R.; 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.V.; Zamyatnin, A.A.; Erofeev, A.S.; Gorelkin, P.V.; Beloglazkina, E.K.; Zyk, N.V.; Khazanova, E.S.; Majouga, A.G.

Статья опубликована в высокорейтинговом журнале

Информация о цитировании статьи получена из Web of Science, Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 4 марта 2022 г.

Авторы: 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 A.D., Chepikova Olga E., Kovalev Sergei V., Zamyatnin Andrey A., Erofeev Alexander S., Gorelkin Petr V., Beloglazkina Elena K., Zyk Nikolay V., Khazanova Elena S., Majouga Alexander G.
Журнал: Journal of Medicinal Chemistry
Том: 64
Номер: 23
Год издания: 2021
Издательство: American Chemical Society
Местоположение издательства: United States
Первая страница: 17123
Последняя страница: 17145
DOI: 10.1021/acs.jmedchem.1c01157
Аннотация: Prostate cancer is the second most common type of cancer among men. The main method of its 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 performed the synthesis of 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. Conjugate demonstrated 77-85% tumor growth inhibition level on 22Rv1 (PSMA+) xenografts in comparison with 37% on PC-3 (PSMA-) xenografts in a single dose of 0.3 mg/kg and a sufficiently high therapeutic index of 21. Acute, chronic, subchronic toxicities and pharmacokinetics have shown that the synthesized conjugate is a promising potential agent for chemotherapy of prostate cancer.
Добавил в систему: Мачулкин Алексей Эдуардович

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Synthesis, characterization and preclinical evaluation of small-molecule prostate-specific membrane antigen targeted monomethyl auristatin E conjugateстатья