The aim of the study was to carry out a comparative morphological and immunohistochemical analysis of peripheral non-small cell lung cancer, which served as a source of a xenograft tumor, and tissues of the third generation of a tumor that developed in animals.Material and methods. We used 19 athymic BALB/c nu/nu mice, which were intraperitoneally injected with 1×106 CD8+ after sublethal irradiation in accordance with the humanization protocol. The transplantation of a tumor obtained from a 64-year-old patient was carried out three times consecutively. Samples of the original and xenograft tumors were automatically stained with hematoxylin and eosin, rabbit anti-CK7, anti-TTF, and anti-Ki67 antibodies. The evaluation of histological samples was carried out in accordance with the WHO recommendations (2015).Results. It has been established that a third-generation tumor developing in the body of athymic humanized mice retains the morphological and immunohistochemical features of the patient's original tumor. The described approach may be used in preclinical and personalized studies in fundamental pharmacology and molecular oncology.

We studied the antitumor activity of two compounds - derivatives of pyridinecarboxylic acids with laboratory codes LHT-13-19 and LHT-17-19 in two cancer cell cultures: colon HT29 and estrogen-sensitive breast cancer MCF-7. Сompounds were synthesized in the department of chemistry, technology of synthetic drugs and analytical control of VNС BAV (Russia). A possible mechanism for the development of secondary chemoresistance was determined on the organoid model of triple-negative breast cancer, provided to us by scientists from the FGBI “N.N. Dmitry Rogachev" of the Ministry of Health of Russia. Both compounds were shown to be cytotoxic against two human neoplasias with an inhibitory concentration of 1.3 × 10-7 for substance LHT-17-19 and LHT-13-19 – 7.6 × 10-3 M for colon cancer HT29 and 1.6×10-5 (LHT-17-19) and 3.8×1 (LHT-13-19) for MCF-7 breast cancer. During the formation of secondary resistance of triple-negative breast cancer cells to LHT-13-19, the reverse transport of compound molecules is activated, as evidenced by the increase in the concentration of the substance in the cultivation medium after washing the three-dimensional culture. Under the same experimental conditions, although secondary resistance to LHT-17-19 is formed, no efflux of molecules into the medium is observed, which indicates that in this case other mechanisms not related to reverse transport may be involved.

The work identified potential molecular targets for the implementation of the antitumor effect of a new domestic compound, an analogue of pyridine LHT-13-19. Using the "Autodock 4.2" software environment, flexible receptor-directed molecular biological docking was carried out in virtual reality, which makes it possible to most accurately predict the formation of a complex between a molecular structure and a biological target in real conditions of a specific biological system. For molecular docking, three-dimensional structures of the epidermal growth factor receptor (EGFR, PDB ID: 1M17, 4KN2) from the open electronic library Protein Data Bank (USA) were used. The ligands were prepared using the MGL Tools 1.5.6 software environment, and their optimization was performed using the Avogadro software (USA). The molecule of the compound, an analogue of pyridine nucleoside, was synthesized in the Department of Chemistry, Technology of Synthetic Medicines and Analytical Control of All-Union Research Center for Biological Active Compounds Safety (Russia). As a result of the experiments, it was found that the LHT-13-19 molecule forms a conformational intermolecular interaction with the active centers 1M17, 4KN2 of the epidemic growth factor EGFR. The affinity is based on the formation of hydrogen and electron-acceptor bonds, characterized by high values of the scoring function and free energy value. Moreover, in terms of the strength of the affinity, the LHT-13-19 substance is not inferior to the reference molecule erlotinib.

Abstract. In the work, a pre-experimental screening of pyridinecarboxylic acid derivatives was performed by the PASS program, The work identified potential molecular targets for the implementation of the antitumor effect of a new domestic compound, an analogue of pyridine LHT-13-19. Using the "Autodock 4.2" software environment, flexible receptor-directed molecular biological docking was carried out in virtual reality, which makes it possible to most accurately predict the formation of a complex between a molecular structure and a biological target in real conditions of a specific biological system. For molecular docking, three-dimensional structures of the epidermal growth factor receptor (EGFR, PDB ID: 1M17, 4KN2) from the open electronic library Protein Data Bank (USA) were used. Molecules of compounds - pyridine derivatives LHT-13-19, LHT-16-19 and LHT-17-19 were synthesized in the Department of Chemistry, All-Union Research Center for Biological Active Compounds Safety (Russia). As a result of the experiments, it was found that all the studied molecules have inhibitory activity against proto-oncogenic kinases, however, in terms of the totality of predictive characteristics, as well as the likelihood of forming an antitumor effect, LHT-17-19, which was studied in docking studies, turned out to be the most promising compound. It was shown that LHT-17-19 has a high affinity for the epidermal growth factor kinase receptor EGFR-K, exhibits an affinity for the CSF1 receptor system, superior to that of all comparators - imatinib, erlotinib and pemetrexed. Also, in the process of docking approach and subsequent docking with the active site of tyrosine kinase EGFR-K and the human folate receptor FOLR2, an additional hydrogen bond is formed inside the LHT-17-19 molecule between the hydrogen proton of the amino group and the oxygen atom of the carbonyl group with atomic distances of 2.21 Å and 2 .49 Å, respectively.