Final Report Summary - P53LAZARUS (Tumour suppressor p53: structure, stability and novel anti-cancer drug development)
The tumour suppressor p53 destroys cancer cells by activating apoptopic pathways. For cancer cells to survive, p53 or its pathways must be put out of action. p53 is directly inactivated by mutation in some 50% of human cancers and its pathways impaired in the remainder or itself destroyed by other proteins induced in cancer cells. A major goal in therapy is to find novel anti-cancer drugs that can reactivate mutant p53 so that cancer cells are once again eliminated. We had discovered that some 30-40% of p53's oncogenic mutations inactivate it by lowering its stability so causing it to denature and aggregate at body temperature. Those mutants are possible targets for therapy as some are stable and active at lower temperatures. The goals of the project were to understand the basic principles of how to reactivate mutant p53 and and possibly find small molecules that might act as lead compounds for drug development. We pursued a programme of basic research to understand the process of how p53 denatures and aggregates and how aggregation could be prevented. In particular, we examined a particular mutant, p53Y220C, which is a most favourable paradigm because the mutation Y220C causes a surface cavity that is potentially druggable and is not present in wild-type protein. We showed how designed small molecules could bind in the mutational pocket and stabilise the protein in vitro and reactivate it in cancer cell lines. We explored the principles of improving the design of those small molecules. The holy grail is to find small molecules that stabilise a wide range of unstable oncogenic mutants, and we have discovered a novel class of such reagents. The major achievements have been: demonstrating that it is feasible to reactivate mutant p53 in cancer cells, which will stimulate the search for novel anti-cancer drugs; the discovery of a new mechanism of protein aggregation, which leads to the inactivation of p53 and is likely to be more general for the aggregation of other proteins; the pioneering of new types of compounds that are suitable for binding to and stabilizing proteins, such as halogen-enriched compounds; extending targets and mthods for stabilizing proteins, from combining experiment and simulation; discovery of a new class of mild alkylating agents with anti-cancer activities, the 2-sulfonylpyrimidines.