Reactivating mutant p53 using small molecules as zinc metallochaperones: Awakening a sleeping giant in cancer

Adam R. Blanden, Xin Yu, Stewart N. Loh, Arnold J. Levine, Darren R. Carpizo

Research output: Contribution to journalReview articlepeer-review

44 Scopus citations

Abstract

Tumor protein p53 (TP53) is the most commonly mutated gene in human cancer. The majority of mutations are missense, and generate a defective protein that is druggable. Yet, for decades, the small-molecule restoration of wild-type (WT) p53 function in mutant p53 tumors (so-called p53 mutant 'reactivation') has been elusive to researchers. The p53 protein requires the binding of a single zinc ion for proper folding, and impairing zinc binding is a major mechanism for loss of function in missense mutant p53. Here, we describe recent work defining a new class of drugs termed zinc metallochaperones that restore WT p53 structure and function by restoring Zn2+ to Zn2+-deficient mutant p53.

Original languageEnglish (US)
Pages (from-to)1391-1397
Number of pages7
JournalDrug Discovery Today
Volume20
Issue number11
DOIs
StatePublished - Nov 1 2015

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery

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