Restoring Activity in Cancer-Preventing Proteins

  • ChemPubSoc Europe Logo
  • Author: Chemistry – A European Journal
  • Published Date: 29 December 2018
  • Source / Publisher: Chemistry – A European Journal/Wiley-VCH
  • Copyright: Wiley-VCH Verlag GmbH & Co. KGaA
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Over 50 % of cancer diagnoses are attributed to a loss of function in the p53 protein which functions as a tumor suppressor. Therefore, the pharmacological reactivation of p53 is a key target in cancer research. Mutations due to cancer often render this protein inactive due to local protein unfolding, aggregation, and a loss of structural zinc ions located within the protein's core DNA-binding domain.

Christian Gaiddon, Université de Strasbourg, France, Jeffrey J. Warren, Tim Storr, Simon Fraser University, Burnaby, Canada, and colleagues have developed a series of multifunctional ligands that restore the original wild-type function to mutant p53. The ligand design (pictured) includes iodinated phenols (blue) to stabilize a mutant-induced cavity and inhibit protein unfolding, and metal chelators (grey) which bind and increase intracellular Zn2+ to repopulate the metal-depleted site.

Cytotoxicity assays showed that the molecules were highly cytotoxic on a wide range of cancer cell lines. The lead small molecule in this study selectively induced apoptosis (programmed cell death) in a mutant p53 cell line, reduced levels of unfolded mutant p53, and recovered transcriptional p53 function. Overall, according to the researchers, the multifunctional scaffolds have the potential to restore wild-type function to mutant p53, showing promise for cancer treatment.


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