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

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 Zn(2+) to Zn(2+)-deficient mutant p53.

SUBMITTER: Blanden AR

PROVIDER: S-EPMC4922747 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Blanden Adam R AR Yu Xin X Loh Stewart N SN Levine Arnold J AJ Carpizo Darren R DR

Drug discovery today 20150720 11

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 m ...[more]

PMID: 26205328

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