Abstract

A number of proteins that interact with telomeres have been identified in human cells, indicating the high plasticity of human nucleoprotein complex organization. The most important complex is the "shelterin" complex, which consists of six proteins: TRF1, TRF2, TIN2, POT1, TPP1. The TRF1 and TRF2 directly bind to telomeric double-stranded DNA and the TIN2 protein. The TIN2 protein also binds to the TPP1 protein, stabilizing the structure of the entire "shelterin" complex. The PhD thesis presents the characterization of the effect of eleven small molecule compounds (B070, B087, B176, B280, B327, A822, A378, A670, A628, ST50, ST2S), which were designed in silico as potential inhibitors of interactions between TRF1-TIN2 and TRF2-TIN2 proteins. Human breast cancer cell lines were used for the studies: MDA-MB-231 (ER/PR-; HER2/Neu-), BT-20 (ER/PR-; HER2/Neu-), SK-BR-3 (ER/PR-; HER2/Neu+), BT-474 (ER/PR+; HER2/Neu+), MCF-7 (ER/PR+; HER2/Neu-) and T47D (ER/PR+; HER2/Neu), which represent the basic molecular subtypes of breast cancer. Experiments were also carried out on primary HMEC cells and material from patients (invasive ductal breast cancer, ER/PR+; HER2/Neu-). Based on the results obtained using molecular biology methods - starting from toxicity tests, through the advanced technique of fluorescent staining using confocal microscopy and SPR technique - two compounds (A822 and B327) were identified as promising, which were included in a patent application.

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