Drug discovery and mutant p53

Abstract

Missense mutations in the p53 gene are commonly selected for in developing human cancer cells. These diverse mutations in p53 can inactivate its normal sequence-specific DNA-binding and transactivation function, but these mutations can also stabilize a mutant form of p53 with pro-oncogenic potential. Recent multi-disciplinary advances have demonstrated exciting and unexpected potential in therapeutically targeting the mutant p53 pathway, including: the development of biophysical models to explain how mutations inactivate p53 and strategies for refolding and reactivation of mutant p53, the ability of mutant p53 protein to escape MDM2-mediated degradation in human cancers, and the growing 'interactome' of mutant p53 that begins to explain how the mutant p53 protein can contribute to diverse oncogenic and pro-metastatic signaling. Our rapidly accumulating knowledge on mutant p53-signaling pathways will facilitate drug discovery programmes in the challenging area of protein-protein interactions and mutant protein conformational control.