Service Communautaire d'Information sur la Recherche et le Développement - CORDIS

Final Activity Report Summary - P53MUT. REACTIVATORS (Computer-assisted drug discovery and biophysical characterisation of mutant reactivators of the transcription factor p53 ...)

The tumour suppressor p53 is mutationally inactivated in some 50% of human cancers. About a third of the mutations lower the melting temperature of the protein, leading to its rapid denaturation. Small molecules that bind to those mutants and stabilise them could be effective anti-cancer drugs.

The mutation Y220C, which occurs in ~75,000 new cancer cases per annum, creates a surface cavity that destabilizes the protein by 4 kcal/mol, at a site that is not functional. We have designed a series of binding molecules from an in-silico analysis of the crystal structure using virtual screening and rational drug design. One of them (PhiKan083) binds to the cavity with a dissociation constant of ~ 150 µM. It raises the melting temperature of the mutant and slows down its rate of denaturation. We have solved the crystal structure of the protein-PhiKan083 complex at 1.5 A resolution.

The structure implicates key interactions between the protein and ligand and conformational changes that occur on binding, which will provide a basis for lead optimisation. The Y220C mutant is an excellent 'druggable' target and hence there is every possibility that an anti-cancer drug could be developed from studies on the Y220C mutant.

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United Kingdom