DEVOCAT

Directed Evolution of Small-Molecule Cancer Therapeutics

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

Genetic alterations are the hallmark of cancer. A European team is investigating a therapeutic strategy that restores the action of a natural anti-cancer gene.

Descrizione progetto (Article)

Cancer remains one of the biggest challenges today, causing 1.7 million deaths annually in the EU alone. It is characterised by genetic heterogeneity which hampers the development of a common treatment approach. Nonetheless, 15-20 % of tumours present with mutations in the tumour suppressor protein p53. A key regulator of the cell cycle, p53 mutations destabilise the protein and inactivate its ability to mediate apoptosis under physiological conditions.

The idea behind the EU-funded 'Directed evolution of small-molecule cancer therapeutics' (DEVOCAT) project is to utilize simple microbes to develop drugs that can restore p53 protein activity and function as an anti-cancer therapy. The approach entails the synthesis of small molecules to restore the three-dimensional folding and function of the mutant p53.

Biosynthesis takes place within microbial cells, leading to a vast array of small-molecule compounds with high chemical and structural diversity. So far, approximately 10,000,000 such compounds have been synthesised and are being screened in a high-throughput genetic system. The output of this system evaluates the ability of each compound to improve the folding of the mutant p53 protein and its function.

The function of the p53 protein will be assessed through different biochemical and biophysical methods. The most promising candidate molecules will be tested in cancer cell lines for their apoptotic capacity.

Overall, the concept of the DEVOCAT study offers a promising alternative to standard approaches for cancer therapeutics discovery. It would be interesting to determine if this approach works in vivo, as cancers are known for their constant ability to evolve and evade cell death.