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
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.
J Med Chem. 2021 Dec 9;64(23):17123-17145. doi: 10.1021/acs.jmedchem.1c01157. Epub 2021 Nov 19.
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.
前列腺癌是男性中第二常见的癌症类型。其主要治疗方法是化疗，化疗具有广泛的副作用。应对这一挑战的解决方案之一是靶向递送至前列腺癌细胞。在此，我们基于单甲基澳瑞他汀E合成了一种新型小分子PSMA靶向缀合物。通过核磁共振光谱研究了其结构和构象性质。对该缀合物进行了细胞毒性、细胞内活性氧诱导以及在肝微粒体和P450细胞色素物种下的稳定性研究。在单剂量0.3 mg/kg时，该缀合物对22Rv1（PSMA(+)）异种移植瘤的肿瘤生长抑制水平为77 - 85%，相比之下，对PC - 3（PSMA(-)）异种移植瘤的抑制水平为37%，且具有足够高的21治疗指数。急性、慢性和亚慢性毒性以及药代动力学研究表明，合成的缀合物是一种有前景的前列腺癌化疗潜在药物。
