Chemical Repair of an Oncogenic Mutation in p53

ASPIRE Award (2023-Present)

Nir London, PhD, The Weizmann Institute of Science, Israel

Nir London, PhD

The tumor suppressor protein p53 is referred to as the “guardian of the genome” because of its central role in controlling cell growth and division. Mutations in p53 are the most common mutations found in cancer, and interestingly, some sites on the protein are significantly more prone to mutations than others. One such mutation introducing a new cysteine residue is found in hundreds of thousands of cancer patients annually and disrupts the function of p53. However, despite our longstanding understanding about p53 and its common mutations found in cancer, the lack of suitable pockets for traditional small molecule drugs has rendered p53 intractable for drug design. There are currently no approved drugs that can correct the function of any p53 mutation effectively.

In this study, Nir London and his group are applying a new strategy for targeting this cysteine mutation with small molecules using a chemical biology approach. By taking advantage of the reactive nature of the cysteine residue, they will design covalent compounds able to react with the mutant cysteine and introduce a correcting chemical moiety to rescue the protein’s function. They have already identified a promising series of compounds that can bind to this cysteine, and they are now pursuing several parallel strategies to convert these compounds into activators that can restore p53 function in cancer cells. This new approach holds potential to lay the groundwork for a personalized medicine to treat the many cancer patients carrying the mutation.