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Using a molecular wedge to stabilise p53

  • Researcher: Dr John Spencer
  • Institution: University of Sussex, Brighton, England
  • Award Amount: £165,779 for 2 years from July 2014
  • Cancer Type: General Cancer Research
Using a molecular wedge to stabilise p53
Usually, the p53 protein is on our side. It works as a monitor, detecting and dealing with potentially cancer-causing DNA damage in our cells. But if p53 is faulty, then a major cell-checkpoint against cancer is out of action. It is no surprise that p53 mutations are common in many different types of cancer.Many p53 mutations affect the stability of the protein. One such mutation, Y220C, is found in around 80,000 new cancer cases every year. p53 proteins containing the this mutation become ‘wobbly’ at body temperature, and are unable to maintain their correct structure for very long. This renders the protein incapable of remaining on guard against DNA damage. Despite the well-known links between p53 and cancer, scientists have found it hard to develop treatments that target the protein.Dr John Spencer in Brighton, UK is a medicinal chemist who is now bringing his talents to the p53 problem. He is working with world leading p53 researchers, Sir Alan Fersht and Dr Andreas Joerger (Laboratory of Molecular Biology, Cambridge). They have been screening for compounds which could act like a ‘molecular wedge’, binding and stabilising ‘wobbly’ p53 proteins with the Y220C mutation. The team have already identified some new compounds which not only stabilise p53, but which have already shown promise of being able to restore p53 function in early lab studies. Dr Spencer will use his new Worldwide Cancer Research award to try and ‘fine tune’ these compounds, improving their anti-cancer activity. He hopes this research will help to establish exciting new possibilities in cancer treatments.
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