Elimination of the tumour suppression activities of p53 is common to all cancers. p53 is inactivated directly by mutation in ~50% of human cancers, and ~30-40% of these oncogenic mutants are just temperature sensitive, ts, being active at lower temperatures. Wild-type p53 spontaneously denatures, with a half-life of 10-20 minutes at body temperature, and ts mutants far faster. The melting temperature and half life of ts oncogenic mutants can be raised by small molecules. The mutant Y220C is particularly propitious for study and as a target for therapy as the mutation makes a druggable cavity. We discovered lead compounds for a novel class of anti-cancer drugs that could be used to treat 70-80,000 new cases of cancer per annum worldwide via reactivating Y220C. I present a programme to understand the basic principles of stabilising Y220C in particular and the thermodynamics and kinetics of ts mutant proteins in general. Such studies may aid the development of lead compounds for reactivating Y220C into prospective drugs and will act as a paradigm for development of the ¿holy grail¿ of a generic p53-reactivating drug. This is not a classical drug screening programme but a fundamental study on how to stabilise proteins whose poor stability causes disease, and which pulls together the twin interests of the applicant in fundamental protein folding and the structural biology of p53. I will investigate the biophysical and structural characteristics of how to stabilize proteins by small molecules using the leads thrown up by the drug-screening programme. Even if none of the leads make it to the clinic, they will be important substrates for the structure-activity studies on the mechanisms of protein stabilization, which will be of general importance.
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Funding SchemeERC-AG - ERC Advanced Grant
SN2 1FL Swindon