Cancer imposes a tremendous socioeconomic burden in modern societies, causing ~1.7 million deaths in the EU annually. 15-20% of these cases occur due to mutations in the oncosuppressor gene p53, which destabilize the protein and inactivate its ability to mediate apoptosis under physiological conditions. Today, no drugs exist which can restore the function of mutant p53 and treat cancer. The present proposal deals with the discovery of potential cancer therapeutics of this type. The topic of the proposed research is the directed evolution of small molecules which can bind to and restore the folding and function of destabilized oncogenic variants of p53 (p53*). These compounds will be selected from libraries of small molecules which will be biosynthesized in microbial cells. Biosynthesis will be carried out using an approach that allows for facile preparation of a very large number of test compounds, which will exhibit high levels of chemical and structural diversity. These small-molecule libraries will then be screened and the compounds which can bind to and improve the folding of p53* will be identified using a high-throughput genetic screen. The effect of the identified compounds on the stability of p53* will be subsequently evaluated in vitro by using biochemical and biophysical methods of protein analysis, and their ability to revitalize apoptosis will be tested in selected human cancer cell lines. The compounds which will be found capable of restoring the stability and apoptosis-mediating function of p53* will become drug candidates against a broad panel of cancers.
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