Abstract 132P
Background
Oncogenic mutation p53(Y220C) is the ninth most common mutation of the p53 protein. Mutation Y220C creates an expanded surface pocket in the DNA-binding domain of p53, due to which the protein is rapidly denatured under physiological conditions. This also negatively affects the effectiveness of p53-dependent signaling and leads to tumor development. In this work, new indazole derivatives were investigated as modulators of mutant p53 activity. We found that the compounds studied were able to initiate an anti-tumor cellular response by activating mutant p53(Y220C).
Methods
Immunocytochemical analysis (ICC) was performed to test the hypothesis that the mutant protein p53(Y220C) can restore its native-like conformation and get reactivated upon interaction with the compounds. The degree of p53 activation was evaluated, and the protein localization in HUH7 p53(Y220C) human hepatocarcinoma cells was determined upon treatment with indazole derivatives.
Results
During the immunocytochemical analysis, images obtained were analyzed using the ImageJ software, and the values of p53 signal intensity were calculated. We found that in comparison with control untreated cells, in samples treated with indazole derivatives increased in levels of p53 were observed mainly in the nucleus, which indicates its activation.
Conclusions
The results of the immunocytochemical analysis demonstrated that indazole derivatives specifically activate mutant p53(Y220C) protein. The compounds represent a promising basis for the development of selective activators not only for Y220C, but also for other mutant forms of p53. The work was funded by grant from the Russian Science Foundation 22-24-20034 and supported by the Kazan Federal University Strategic Academic Leadership Program (PRIORITY-2030).
Editorial acknowledgement
Clinical trial identification
Legal entity responsible for the study
The authors.
Funding
The work was funded by grant from the Russian Science Foundation 22-24-20034 and supported by the Kazan Federal University Strategic Academic Leadership Program (PRIORITY-2030).
Disclosure
All authors have declared no conflicts of interest.
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