77P Targeted compounds for modulation of mutant p53 activity

The study of the role of oncosuppressors in tumor transformations and in the death of tumor cells is an important aspect in many areas of biochemistry. One of the most well-known tumor suppressors is the p53 protein. The function of the p53 protein is to regulate the expression of genes whose products lead to cell cycle arrest and apoptosis. Many types of cancer are associated with inactivation of the tumor suppressor p53 as a result of mutation. The p53Y220C oncogenic mutation it creates an extended surface pocket in the DNA-binding domain. Therefore, the development of targeted drugs to modulate p53Y220C activity is highly relevant. The aim of this work was to evaluate the effectiveness of (1H-pyrrol-1-yl)indazole derivatives as modulators of the activity of the mutant p53Y220C.. In this work the following cell lines were used: human breast carcinoma (MCF7 p53wt, MCF7 p53-/-, MCF7 p53Y220C) and human hepatocarcinoma (HUH7 p53Y220C). Western blot analysis was performed to investigate the effect of indazole derivatives on p53 expression. Immunocytochemical analysis was performed to assess the ability of the studied compounds to induce refolding of the mutant p53Y220C.. According to the results of Western blot analysis, it was revealed that the compounds lead to an increase in the expression of the p53 protein in cell lines with mutant p53Y220C. Immunocytochemical analysis of the HUH7 p53Y220C cell line treated with compounds showed the ability of the studied compounds to induce refolding of the mutant p53Y220C with the acquisition of a conformation corresponding to the wild-type protein. Thus, the results showed that indazole derivatives have a specific effect on cells carrying the p53Y220C mutation and stabilize the mutant protein in a conformation similar to the wild-type protein. The work was funded by the Russian Science Foundation grant 22-24-20034 and supported by the Strategic Academic Leadership Program of the Kazan Federal University (PRIORITY-2030).