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

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, Еkaterina А.; Панкратов, А. А.; Smirnova, G. P.; Borisova, Yulia A.; Pokrovsky, Vadim S.; Колмогоров, Василий; Vaneev, Alexander; Khudyakov, Alexander D.; Chepikova, Olga E.; Ковалев, С. В.; Zamyatnin, Andrey A.; Erofeev, Alexander; Gorelkin, Petr; Белоглазкина, Е. К.; Khazanova, Elena S.; Majouga, Alexander G.

doi:10.1021/acs.jmedchem.1c01157

Cited by 16 publications

(18 citation statements)

References 49 publications

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“…Dichloromethane (DCM) and methanol (MeOH) were purified by distillation, dimethyl sulfoxide (DMSO) was purified by vacuum distillation and stored over 3 Å molecular sieves. Compounds 4 [ 35 ], 15 [ 56 ], 19 [ 35 ], 20 [ 57 ], 23 [ 58 ], 26 [ 57 ], 28 [ 31 ], and 29 [ 56 ] were prepared as described previously. Yields refer to chromatographically and spectroscopically ( 1 H and 13 C NMR) homogeneous materials, unless otherwise stated.…”

Section: Methodsmentioning

confidence: 99%

Aminooxy Click Modification of a Periodate-Oxidized Immunoglobulin G: A General Approach to Antibody–Drug Conjugates with Dye-Mediated Expeditious Stoichiometry Control

Sapozhnikova

Gulyak

Brylev

et al. 2023

IJMS

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A universal approach to the construction of antibody–drug conjugates (ADCs) has been developed. It relies on periodate oxidation of naturally present glycans of immunoglobulin G, followed by oxime ligation and, optionally, copper(I)-catalyzed alkyne-azide cycloaddition for conjugation with a toxic payload. The introduction of highly absorbing cyanine dyes into the linker allows for facile determination of the drug–antibody ratio. We applied this methodology to the synthesis of cytotoxic conjugates of an antibody against the tumor-associated antigen PRAME with doxorubicin and monomethyl auristatin E (MMAE). The resultant conjugates retained their affinity to a large extent, yet their cytotoxicity in vitro varied dramatically: while the doxorubicin-based conjugate did not produce any effect on cells, the MMAE-based one demonstrated specific activity against PRAME-expressing cancer cell lines. Importantly, the latter conjugate constitutes the first reported example of a PRAME-targeting ADC.

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Section: Methodsmentioning

confidence: 99%

Aminooxy Click Modification of a Periodate-Oxidized Immunoglobulin G: A General Approach to Antibody–Drug Conjugates with Dye-Mediated Expeditious Stoichiometry Control

Sapozhnikova

Gulyak

Brylev

et al. 2023

IJMS

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“…Previously, it has demonstrated a high IC50 value of 9 ± 3 nM in comparison with 80 ± 3 nM for 2-PMPA [29]. Conjugates with the fluorescent agents Fam-5, SulfoCy5, and SulfoCy7 [29], as well as the therapeutic agents docetaxel [18] and MMAE [19], have also been previously obtained.…”

Section: Synthesismentioning

confidence: 95%

“…This approach can improve cancer-selectivity and, consequently, the efficacy of the drug. Accordingly, in this work, we focused on the creation of a conjugate for the targeted delivery of abiraterone based on PSMA (prostate-specific membrane antigen) ligands, which successfully proved themselves in the delivery of such therapeutic agents as docetaxel [18] and MMAE [19].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Preclinical Evaluation of Small-Molecule Prostate-Specific Membrane Antigen-Targeted Abiraterone Conjugate

et al. 2022

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Prostate cancer is the second most common type of cancer among men. The main method of its treatment is androgen deprivation therapy, which has a wide range of side effects. One of the solutions to this challenge is the targeted delivery of drugs to prostate cancer cells. In this study, we performed the synthesis of a novel small-molecule PSMA-targeted conjugate based on abiraterone. Cytotoxicity, the induction of intracellular reactive oxygen species, and P450-cytochrome species inhibition were investigated for this conjugate PSMA-abiraterone. The conjugate demonstrated a preferential effect on prostate tumor cells, remaining inactive at up to 100 µM in human fibroblast cells. In addition, it revealed preferential efficacy, specifically on PSMA-expressing lines with a 65% tumor growth inhibition level on 22Rv1 (PSMA+) xenografts after 14-fold oral administration of PSMA-Abi at a single dose of 500 mg/kg (7.0 g/kg total dose) was observed. This compound showed significantly reduced acute toxicity with comparable efficacy compared to AbiAc.

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“…Although it is out of the scope of the present review, it is important to mention alternative tactics that are being explored with the auristatins with the objective of targeting cancer cells in a highly selective manner by means of platforms different from antibodies recognized by tumor antigens. Among these alternative devices, it is worth highlighting low-molecular-weight ligands for antigens such as the prostate-specific membrane antigen (PSMA) [ 129 ] or integrin ανβ 3 [ 130 ], aptamers [ 131 ], gold nanoclusters [ 132 ] or radiolabeled proteins [ 133 ].…”

Section: Chemistry and Biology Of Marine Antibody-drug Conjugatesmentioning

confidence: 99%

Antibody-Drug Conjugates Containing Payloads from Marine Origin

et al. 2022

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Antibody-drug conjugates (ADCs) are an important class of therapeutics for the treatment of cancer. Structurally, an ADC comprises an antibody, which serves as the delivery system, a payload drug that is a potent cytotoxin that kills cancer cells, and a chemical linker that connects the payload with the antibody. Unlike conventional chemotherapy methods, an ADC couples the selective targeting and pharmacokinetic characteristics related to the antibody with the potent cytotoxicity of the payload. This results in high specificity and potency by reducing off-target toxicities in patients by limiting the exposure of healthy tissues to the cytotoxic drug. As a consequence of these outstanding features, significant research efforts have been devoted to the design, synthesis, and development of ADCs, and several ADCs have been approved for clinical use. The ADC field not only relies upon biology and biochemistry (antibody) but also upon organic chemistry (linker and payload). In the latter, total synthesis of natural and designed cytotoxic compounds, together with the development of novel synthetic strategies, have been key aspects of the consecution of clinical ADCs. In the case of payloads from marine origin, impressive structural architectures and biological properties are observed, thus making them prime targets for chemical synthesis and the development of ADCs. In this review, we explore the molecular and biological diversity of ADCs, with particular emphasis on those containing marine cytotoxic drugs as the payload.

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

Cited by 16 publications

References 49 publications

Aminooxy Click Modification of a Periodate-Oxidized Immunoglobulin G: A General Approach to Antibody–Drug Conjugates with Dye-Mediated Expeditious Stoichiometry Control

Aminooxy Click Modification of a Periodate-Oxidized Immunoglobulin G: A General Approach to Antibody–Drug Conjugates with Dye-Mediated Expeditious Stoichiometry Control

Synthesis and Preclinical Evaluation of Small-Molecule Prostate-Specific Membrane Antigen-Targeted Abiraterone Conjugate

Antibody-Drug Conjugates Containing Payloads from Marine Origin

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